J Neuroimmune Pharmacol DOI 10.1007/s11481-015-9620-2

INVITED REVIEW

An Act of Balance Between Adaptive and Maladaptive Immunity in Depression: a Role for T Lymphocytes Catherine Toben 1 & Bernhard T. Baune 1

Received: 25 March 2015 / Accepted: 19 June 2015 # Springer Science+Business Media New York 2015

Abstract Historically the monoaminergic neurotransmitter system, in particular the serotonergic system, was seen as being responsible for the pathophysiology of major depressive disorder (MDD). With the advent of psychoneuroimmunology an important role of the immune system in the interface between the central nervous systems (CNS) and peripheral organ systems has emerged. In addition to the wellcharacterised neurobiological activities of cytokines, T cell function in the context of depression has been neglected so far. In this review we will investigate the biological roles of T cells in depression. Originally it was thought that the adaptive immune arm including T lymphocytes was excluded from the CNS. It is now clear that peripheral naïve T cells not only carry out continuous surveillance within the brain but also maintain neural plasticity. Furthermore animal studies demonstrate that regulatory T lymphocytes can provide protection against maladaptive behavioural responses associated with depression. Psychogenic stress as a major inducer of depression can lead to transient trafficking of T lymphocytes into the brain stimulating the secretion of certain neurotrophic factors and cytokines. The separate and combined mechanism of CD4 and CD8 T cell activation is likely to determine the response pattern of CNS specific neurokines and neurotrophins. Under chronic stress-induced neuroinflammatory conditions associated with depression, T cell responses may become maladaptive and can be involved in neurodegeneration. Additionally, intracellular adhesion and MHC molecule expression as well as glucocorticoid receptor expression within the brain may

* Bernhard T. Baune [email protected] 1

Discipline of Psychiatry, University of Adelaide, 5005 Adelaide, SA, Australia

play a role in determining T lymphocyte functionality in depression. Taken together, T lymphocyte mechanisms, which confer susceptibility or resilience to MDD, are not yet fully understood. Further insight into the cellular and molecular mechanisms which balance the adaptive and maladaptive roles of T lymphocytes may provide a better understanding of both the neuro- degenerative and –regenerative repair functions as present within the neuroimmune network during depression. Furthermore T cells may be important players in restoration of normal behaviour and immune cell homeostasis in depression. Keywords Major depressive disorder . T lymphocytes . CD4+ . CD8+ T cells

Introduction Major depressive disorder (MDD) is one of the most common forms of mental illness. Worldwide 1 in 5 people will be afflicted at some point in their lifetime by a mood disorder principally anxiety or MDD (Bromet et al. 2011). Currently MDD is the leading cause for worldwide morbidity and accountable for almost 12 % of total years lived with a disability (Ustun et al. 2004). As the prevalence of MDD continues to rise it has become the fourth leading contributor to the global burden of disease (Reddy 2010). About 10 years ago, it was predicted that by the year 2030 MDD would become the world’s second leading cause of disability (Lopez and Mathers 2006). Unfortunately this level was already reached in 2013. Despite its high prevalence and socioeconomic impact, relatively little is known about its pathophysiology. With a disease course that is accompanied by individual alterations in multiple molecular and cellular pathways in addition to structural and functional brain changes, MDD remains a

complex and heterogeneous disorder. Continued research is providing evidence for the role of both genetic and environmental factors directing development of this multifactorial mood disorder. Secondary effects include associated comorbidities such as cardiovascular disease, suicidal ideation and substance abuse. Currently almost a third of depressed patients are unresponsive or intolerant to the use of conventional antidepressant therapy, which targets the monoaminergic neurotransmitter pathways (Greden 2001; Trivedi et al. 2006; Rush 2007). Interestingly, treatment resistant patients are more likely to exhibit an activated immune system (O’Brien et al. 2007). Similarly, patients that are less likely to show a response to treatment often exhibit an elevated inflammatory marker profile further suggesting an integral role of the immune system in depression (Sluzewska et al. 1997; Lanquillon et al. 2000; Fitzgerald et al. 2006; Harrison et al. 2009). Evidence for a Role of Innate and Adaptive Immunity in Depression Most of the literature on an immune response in MDD has focused on the activation of the initial immune response including measurements of cytokines from non-specific and phagocytic cells such as monocytes/macrophages. This first line of defence is generally broad acting but short lived. Before its defences are overwhelmed it communicates via specific cell signalling molecules with the advanced and adaptive immune arm. The adaptive immune response provides flexibility and immunological memory but is dependent upon elements of the innate immune arm for initiation and direction of responses. Humoral or B cell mediated antibody mechanisms as well as T cell mediated immunity are part of this adaptive immune arm repertoire. Accumulating evidence as presented in recent reviews (Miller 2010) point to an active T cell involvement in MDD contributing to the progression and resolution of a chronically activated immune system. Brief Overview of the Cytokine Model of Depression Originally described as melancholia by Hippocrates, MDD was first characterised as an illness response to ‘sickness behaviour’ by a veterinarian (Hart 1988). This response typically induced by acute infection or tissue injury is characterised by fatigue, pyrexia, anhedonia and loss of appetite, psychomotor impairment, impaired cognitive functioning and depressed mood. Classified as a mood disorder, MDD shares these basic symptoms with sickness behaviour. Other clinical features of depression include the three symptom dimensions which are melancholia, anxiety or psychosomatic such as increased sensitivity to pain, (Leonard and Maes 2012). While these symptoms are also shared with sickness behaviour its additional symptom of significant pyrexia while also displaying a more

acute and short lasting behavioural pattern distinguish it from the clinical symptoms of depression. However, both share similar underlying immunological pathways which may explain the phenomenological overlap (Maes et al. 2012). The contribution of an activated immune response to the pathophysiology underlying MDD was first defined by (Smith 1991) as the ‘macrophage theory of depression’ which proposed that secretion of macrophage cytokines including IL-1β and TNFα led to some cases of MDD. This was further extended by (Maes et al. 1991, 1992b, c) and others who identified increased inflammatory biomarkers in peripheral blood of depressed patients including cytokines and acute phase reactants such as C-reactive protein (CRP). A large body of evidence supporting this cytokine theory of depression points to the multifaceted roles of cytokine signalling within the CNS during depression. These include neuroendocrine function, neurocircuitry, altered neurotransmitter metabolism and neurogenesis as discussed in greater detail in reviews by (Dantzer et al. 2008; Haroon et al. 2012). Furthermore significant associations between inflammatory biomarker concentration and depressive symptoms have been found (Motivala et al. 2005). Although inflammatory biomarkers are not always elevated in depressed patients there is evidence to suggest this may be due to discrepancies between cytokine sampling as well as influence from the circadian rhythm. However, recent meta-analyses strengthen the link between an activated immune response and MDD by measurements of elevated peripheral immune biomarkers in particular interleukin (IL)-6, tumour necrosis factor (TNFα) and CRP (Zorrilla et al. 2001; Dowlati et al. 2010). The second line of evidence for a role of inflammation in MDD comes from studies administering cytokines or endotoxins such as lipopolysaccharide (LPS) to both humans as well as animal models of depression (Dunn et al. 2005; DellaGioia and Hannestad 2010; Stepanichev et al. 2014). One in four nondepressed hepatitis C patients receiving therapeutic administration of IFN-α will develop depressive symptoms associated with increased IL-6 levels (Udina et al. 2012) while over 45 % of non-depressed cancer patients treated with recombinant IL2 will develop MDD (Denicoff et al. 1987; Renault et al. 1987). Conversely, exogenous administration of IL-1β or TNFα in healthy animals induces ‘sickness behaviour’ (Anforth et al. 1998; Dantzer 2001; Kaster et al. 2012) while knocking out IL-1β is protective (Bluthe et al. 2000). Additionally, depression is seen to occur more frequently in those with medical disorders caused by a dysregulated immune system as seen in rheumatoid arthritis (Dickens et al. 2002) and multiple sclerosis (Minden and Schiffer 1990). Although this ‘sickness response’ can be regarded as an adaptive immune response to infection reversible once the pathogen has been eliminated, this is not the case for depression. It is conceived that during stress induced depression the continuation of a dysregulated and activated immune response is a

maladaptation of the cytokine-induced sickness occurring in the context of vulnerable individuals. The common theme between the two is conservation and redirection of energy necessary to fight both internal and external conflicts (Maier and Watkins 1998). However, sickness behaviour is a component of depression but not part of it therefore it is best to regard the pro-inflammatory cytokine induced sickness response as a form of vital exhaustion rather than depression (Janszky et al. 2005; Maes et al. 2012). Consequently utilising sickness behaviour, as an animal model of MDD is limited and should be used with caution (Dunn et al. 2005). Roles of T Cells in Depression In a large proportion of cases, MDD symptoms develop in the context of psychosocial stress. With the advent of psychoneuroimmunology (Solomon and Moss 1964; Ader 1981) the intricate and complex relationship between the mind and resulting behaviour, neuroendocrine and immune systems is becoming better understood. It is within this context that the traditional view of the immune system’s primary objective to protect the host from pathogens and invaders has been superseded by the more holistic understanding of its involvement in whole body homeostasis as well as cross-talk with other regulating body systems such as the brain. With a focus on this bidirectional communication network between the CNS and immune system the immune system operates as a diffuse sensory organ (Blalock and Smith 2007) informing the brain of physiological events within the body while simultaneously receiving signals from the brain. Clues for involvement of the brain in modulating the immune system were identified as early as in the 18th and 19th century when Galen observed that cancer occurred more often in ‘melancholic’ women (Kowal 1955; Leonard et al. 1987). Subsequent research has investigated the neuroimmunological mechanisms within a range of CNS disorders, including conventional autoimmune diseases, brain trauma injuries, stroke, neurodegenerative diseases and depression (Klegeris et al. 2007) (Capuron and Dantzer 2003) These clinical observations point towards a more complex model of depression in which over time the systemic innate immune mechanisms are communicating with the adaptive or acquired immune arm. Whilst the older literature supported the notion of T c el l s be i n g i nn oc e nt v i c t i m s or b y s t a n de r s o f neuropathophysiology, new data is demonstrating that T cells play a pivotal role in both the development and resolution of depression. The traditional view considered the CNS as an immune privileged site as it was thought that the blood brain barrier (BBB) precluded peripheral immune cells from entering the brain as well as CNS specific cells such as microglia and astrocytes being subjugated by the immune system (Carson et al. 2006). It is now becoming evident that the crosstalk

between the CNS and immune system involves active participation in immune regulation by microglia, astrocytes and neurons (Tian et al. 2012). Therefore it is now by virtue of the differing and specialised immune responses between the brain and immune system and not any physical barriers that the CNS has attained status as an immune privileged site (Galea et al. 2007; Tian et al. 2009). It is becoming clear that the roles of T cells within the CNS are varied and include continual immune surveillance, regulation of neurogenesis (Ziv and Schwartz 2008) as well as contributing to maintenance of cognition (Schwartz and Kipnis 2011), learning and emotional behaviour as shown in T cell deficient mice (Kipnis et al. 2004). Although neurogenic induced stress as also found in MDD, can result in migration of peripheral lymphocytes across the BBB (Dhabhar 2008) meta-analyses (Herbert and Cohen 1993; Zorrilla et al. 2001) report a statistically significant decrease in in vitro T cell responses from both stressed and depressed individuals. Unclear as yet are how the T cells contribute to the adaptive and maladaptive immune responses during MDD. The Present Systematic Review While most studies have concentrated on CD4 and CD8 characterisation in addition to mitogen induced T cell proliferation, not many investigations have directly examined the function of relevant T cell subsets. This would include the intracellular expression of cytokines as well as the role of regulatory T cells in the regulation of neuroinflammation and newly defined CD4+T cell subsets such as Th17. Although earlier findings suggest global suppression of the immune system with decreased T cell numbers and impaired function during depression, it is most likely that the immune system is adaptive in the context of depression duration and severity and its inherent aim is to establish a return to homeostasis of the cellular and humoral immune arms. Given that the last extensive meta-analyses on immune function in depression (Zorrilla et al. 2001) and the narrative review on depression and a role for T cells (Miller 2010) are going back at least 5 or more years, the purpose of this review is to identify more recent literature reporting clinical as well as basic science data supporting the adaptive and maladaptive T cell mechanisms during depression.

Method Article Identification Articles for the systematic review were identified through electronic literature searches using logic grids. Logic grids were designed by implementing the unique database field

codes for the main combined search terms of major depression and T cells as seen in Table 1. The selected search terms were then entered into 3 databases including Pubmed, EMBASE and Psych Info with English and German filters. Peer reviewed articles retrieved from these combined databases were published from inception until Dec 2014. Review articles were also screened.

Duplicate studies from the combined database search were removed. Data including objectives/aims of study, demographic/sample size, type of specimen analysed, method of T cell analyses followed by results of direct T cell outcomes as well as other related neuroimmune outcomes were extracted. A summary of studies reporting T lymphocyte count and in vitro mitogenic responses is presented in Tables 2 and 3.

Inclusion and Exclusion Criteria and Search Strategy

Results Articles were included that met inclusion/exclusion criteria. Both human and animal studies were included in this review. The first criterion included articles, which were peer-reviewed and complete including editorials that reported data and excluded non peer-reviewed articles (such as dissertations, conference abstracts and posters). The second criterion restricted studies to include direct T cell measurements and excluded cytokine only studies without T cell information or immune measures following dexamethasone suppression. The third criterion, specifically in human studies, included MDD cases lacking an infectious aetiology (such as latent viral infection), and healthy controls and excluded reporting of depressive symptoms without a MDD diagnosis (such as perinatal, PTSD or BPD), or only MDD or only healthy volunteers (MDD lacking controls). The fourth criterion was that human studies with participant’s ages ranging from 18 to 65 years were included. Table 1 Search terms used in all 3 databases including English and German titles and abstracts searched Inclusion criteria

Exclusion criteria

Depression Depressive disorder Major depression Mood disorder MDD Melancholia Clinical depression Treatment resistant depression Endogenous depression Depressive psychosis Atypical depression Unipolar depression T cell T lymphocyte Cellular immunity Cellular immune response Cell mediated immunity Immune modulation Thymus dependent lymphocyte

Alzheimer’s disease Mixed mania and depression Borderline personality disorder Cardiovascular disease Diabetes Dementia Depressive psychosis Dysphoria Dysthymia Heart disease Inflammatory disease Involutional depression Late life depression Major affective disorder Masked depression Medical illnesses Minor affective disorder Mixed anxiety and depression Multiple sclerosis Neurological disorder Perry syndrome Postoperative depression

Logic grids were generated by implementing unique database field codes for the above inclusion and exclusion criteria for Pubmed, EMBASE and Psych Info

T Cell Roles in Maladaptive Immune Responses During MDD Effects of T Cell Number, In Vitro Proliferative Response and Activation Status Under Maladaptive Conditions Psychogenic stress induced MDD is associated with a dysregulation of the immune system as characterised by a decreased T cell number and in vitro proliferative response. However, this effect can become maladaptive during chronic stress as seen in MDD and proliferation can increase over time. We found only 1 study out of 23 (Altshuler et al. 1989) to have reported increased T cell proliferation. Further T cell subtyping enables the origin of the T cell response to be identified. Only 5 out of a total of 23 studies were found to have carried out T cell subtyping. While three studies showed an increase in the % of CD4+ T cells, only two studies reported an increased CD4/CD8 ratio (Maes et al. 1992a), (Muller et al. 1993) (Darko et al. 1989; Seidel et al. 1996; Rothermundt et al. 2001). Interestingly only one study simultaneously measured in vitro T cell proliferation, which remained unchanged between MDD patients and controls (Darko et al. 1989). These studies point to a role for CD4+ T cells in being involved in perpetuating the neuroinflammation as seen in MDD and can be regarded as being part of the maladaptive T cell response. Animal studies utilising the chronic mild stress model (Hong et al. 2013) have demonstrated that depressive like behaviour is closely related to an imbalance between pro-inflammatory CD4+ Th17 and regulatory T cells (Tregs). As such, the presence of elevated IL-6 levels as found in depression like behaviour provides a favourable environment for Th17 cells. In a separate study (Beurel et al. 2013) depression inducing stimuli albeit acute led to an increase in brain Th17 cells. Conversely, transfer of Th17 cells into naïve WT mice led to depressive like behaviour and blocking Th17 cells provided resistance to depressive like behaviour. Both these studies suggest that increased Th17 found either in the peripheral immune organs or brain increases susceptibility to MDD and are thereby representative of maladaptive T cell behaviours and as represented in Figs. 1 and 2. Whilst some of the earlier studies (Maes et al. 1993, 1994a) reported an increase in CD2+HLA-DR+ T cells and CD7+CD25+

Table 2

Overview of studies on lymphocyte count and in vitro mitogenic induced lymphocyte proliferation in MDD

Author

Lymphocyte count

In vitro mitogenic induced lymphocyte proliferation

Kronfol et al. 1983 Schleifer et al. 1984 Kronfol and House 1984 Albrecht et al. 1985

Not measured ↓ ↔ Not measured

↓PHA, ConA, PWM *↓PHA, PMA, PWM ↓PHA, ConA, PWM ↔PHA, ConA, PWM*

Kronfol et al. 1986

Not measured

Irwin et al. 1987 Darko et al. 1988 Darko et al. 1989 Altshuler et al. 1989 Kronfol and House 1989 Maes et al. 1989 Schleifer et al. 1989 Levy et al. 1991 Maes et al. 1991

↔ ↑CD4+% Not reported Not reported ↓%lymphocytes, ↔T cell subsets ↔ ↔ ↔CD4+%or CD8+% Not reported

Andreoli et al. 1992 Marazziti et al. 1992

↓*

↓PHA, ConA, PWM MDD+↑UFC/↓PHA, ConA MDD+normal UFC Not measured ↔ConA, PHA ↓ConA*/↔PHA *low dose only ↑ PHA ↓PWM, ConA/↔PHA Not measured ↔PHA, ConA, PWM *hospitalised MDD ↓PHA, ConA/↔PWM ↓ PHA, ConA, PWM* *only minor depression, MD-M & MD+M **↓prolif due to UFC not MDD severity ↔ PHA, ConA, PWM *MDE vs MDE+PD

↓CD3+, CD8+* Not reported ↑CD4/CD8 ratio (↑CD25+) ↔

Not measured ↔PHA, ConA, PWM* Not measured ↔PHA*

Wodarz et al. 1991 Maes et al. 1992a Hickie et al. 1993

McAdams and Leonard 1993 ↓%lymphocytes Muller et al. 1993 ↑CD3+% & CD4+% ↑CD4/CD8 ratio ↔CD8+% Spurell and Creed 1993 Not measured Maes et al. 1993 ↔ (↑CD2+HLA-DR+, CD7+CD25+)* Maes et al. 1994a ↔ (↑CD2+HLA-DR+, CD7+CD25+)* Anesi et al.1994 ↔* Bauer et al. 1995 ↔ Perini et al. 1995 ↔ Seidel et al. 1996 ↑D15 & D43* Ravindran et al. 1998 ↔CD4+, CD8+ Rothermundt et al. 2001 ↑* Nunes et al. 2002 Pavon et al. 2006 Farid Hosseini et al. 2007

↔ ↑CD8+ ↔

Notes

*hospitalised *letter to editor *MD/endogenous, MD/non-endogenous vs controls

*No access/as per abstract *included 2/10 MD+BPD *No access/as per abstract *trend for ↓MD+M vs controls

↓PHA & after recovery Not measured in MDD only in affective psychosis ↓PHA* Not measured Not measured ↓* ↔PHA, ConA, PWM Not measured Not measured Not measured Not measured ↓PHA* Not measured Not measured

*MDD vs grp anticipating bereavement (stress) *Melancholics vs controls *Melancholics vs controls *No access/as per abstract

*longitudinal study *MD+non-melancholic but not MD+M vs controls *in both very severe & high MDD Elevated Th2 CK (IL-4, IL-13)

The majority of studies investigating peripheral T cell number in MDD used ficoll hypaque gradient purified lymphocytes. Some studies phenotyped T cell subsets as noted in the table. Peripheral T cell mediated immune responses were measured by in vitro mitogenic stimulation. The notes include information on subtypes of MDD included in the study

activated T cells in melancholic patients compared to controls and minor depressives, this has not been substantiated with more recent studies. It is envisaged that as T cell numbers increase their activation status will also be upregulated during neuroinflammation in MDD. This would include upregulation

of adhesion molecules, which enable migration and homing into specific tissue sites in addition to interaction with different target cells. However, so far no studies have investigated this. An early report by (Maes et al. 1992a) suggests that depression is characterised by CD4+CD45RA- memory T

Table 3 Number of studies on increased, decreased or unchanged lymphocyte count and lymphocyte proliferation responses

Lymphocyte count

Lymphocyte proliferative response

No. of studies Only one measure Both count & proliferation

↓ 1 4

↔ 7 7

↑ 5 1

↓ 5 8

↔ 2 4

↑ 1 0

measures Total no. of studies

5

14

6

13

6

1

Summarises the number of studies in presented in (Tables 2 and 3) reporting either a ↓ decrease, ↔ unchanged or ↑ increase in either lymphocyte count or lymphocyte proliferative response Abbreviations: MDE+PD major depressive episode + panic disorder, UFC urine free cortisol, MD-M major depression –melancholia, MD+M major depression+melancholia, MD+BPD major depression+bipolar disorder

cells. Interestingly, no difference between controls and MDD of CD4+CD45RO+ memory T cells was found in a longitudinal study over 43 days (Seidel et al. 1996). While memory T cells are generally generated post infection, the presence of adrenergic receptors on all lymphocytes suggests that psychogenic induced depression could also affect T cell number and activation status (Yu et al. 1999). Whether memory T cells have a role to play in MDD pathophysiology as part of their adaptation to the course of MDD and in particular relapsing remitting depression remains to be investigated. Caution should be taken when comparing human memory T cells expressing the memory type CD45 isoform i.e. either RO or RA as these subpopulations of memory T cells are not uniform in their functional or maturational properties (Berard and Tough 2002; Ohara et al. 2002). It is worthwhile to note that maladaptive T cell roles appear to also be regulated by telomere shortening which has been reported in depression (Simon et al. 2013) and more recently by (Karabatsiakis et al. 2014). These studies found that CD8+ but not CD4+ T cells exhibit shortened telomeres in MDD when compared to controls. Although a relatively small cohort containing only women was studied, this does suggest that T cell functioning in MDD may be affected by telomere shortening or that telomere length may be a marker of disease susceptibility. These studies also imply that any dysfunctional T cell roles are not simply a representation of the disease consequence but may also be attributable to their active participation in the immune response as seen in MDD.

Effects of T Cell Enzyme Activity and T Cell Interactions with Neuroprotective Growth Factors Under Maladaptive Conditions Any dysregulation in the T cell response during MDD would also incorporate altered T cell enzymatic activity. Furthermore enzymes involved in T cell co-stimulation (Elgun et al. 1999) have been found to be reduced during MDD including dipeptidyl peptidase IV (DPPIV) activity. Oxidative stress whether increased or decreased is another reported feature of MDD and this has been shown in purified lymphocytes

including T cells to lead to increased anti-oxidase enzymes as well as cytoplasmic redox sensitive transcription factors including NFΚB, which is involved in regulating inflammatory genes (Lukic et al. 2014). A further recent study (Suzuki et al. 2010) found the lipoprotein ApoE receptor2 mRNA to be down-regulated in lymphocytes from the MDD group when compared to controls. This was however not correlated with duration of illness and may only serve as a biological trait marker and not as a functional mechanism for lipoprotein mediated immune responses. Neuroprotective growth factors (NGF) are important in facilitating the preservation of neuronal structure and function by promoting neuron survival, plasticity, neurogenesis and synaptogenesis. As mediators of neuroprotective mechanisms they essentially aim to halt or stop neurodegenerative processes including increased oxidative stress, and inflammatory changes. Previous publications have focused on BDNF found in association with structural brain changes from post-mortem studies however more recent studies show BDNF to be decreased in serum from MDD vs. controls supporting the notion for its bidirectional movement between the brain and the blood. Of the few studies which investigated the putative roles of NGFs in the context of T cells in MDD, 2 found brain derived neuroprotective factor (BDNF) mRNA to be decreased in isolated lymphocytes pointing to a potential source of peripheral BDNF (Pandey et al. 2010) and as depicted in Fig. 2. Although this population of cells does not distinguish between T, NK, NKT and B cells, it does for the first time present data on NGF gene expression in peripheral immune cells including T cells and a potential maladaptive T cell mechanism. However, whether a decreased serum level is related to a decreased T cell synthesis is unclear as synthesised BDNF is stored in platelets.

T Cell Roles in Adaptive Immune Responses During MDD Effects of T Cell Number, In Vitro Proliferative Responses and Activation Status Under Adaptive Conditions While maladaptive T cell responses occur during current depression these return to more adaptive responses during

However, changes in T cell mitogenic responses from crosssectional studies may not be physiologically significant until longitudinal studies are conducted to enable utilisation of these results as biomarkers for depression or depression-prone individuals. The majority of studies did not phenotypically distinguish between the main T cell subsets including CD4+Thelper and CD8+cytotoxic T cells thereby not allowing for a discrimination of responding cell populations. Two studies (Kronfol and House 1989; Schleifer et al. 1989) used immunofluorescent labelling of T cell subsets for microscopy while another (Andreoli et al. 1992) utilised flow cytometry although specific T cell mAbs used were not reported. These studies, which did include differential labelling, found no significant difference between MDD and T cell subsets when compared with controls. No studies investigated direct T cell subset proliferation or cell viability as for example by incorporating flow cytometric CFSE assessment or live/dead cell stains respectively. A particular disadvantage of employing the 3H thymidine incorporation method is that it does not provide any information on the contribution of activation induced cell death. As a result decreased lymphocyte proliferation responses from 3 H thymidine which is incorporated into the DNA of proliferating cells needs to be interpreted with caution as it may be due to several factors including overall diminution in T cell proliferation, decrease in proliferation of a specific subset of T cells or T cell lymphopenia or under-representation of T cells in the PBMC pool. Of the 13 studies investigating lymphocyte count in addition to T cell proliferative responses, four studies showed a decrease in lymphocyte numbers while seven reported unchanged numbers. In the total 23 studies investigating lymphocyte counts, including the 12 mentioned above, over half of these studies were found to be unchanged in MDD. Two others reported no change while one study reported a decrease in % CD8+T cells another investigation found an increase in CD8+ T cells.

Fig. 1 Flow diagram for inclusion of articles. Legend: Combining the 3 database searches using the specific field codes 689 articles including were retrieved of which 89 empirical articles remained after screening for inclusion and exclusion criteria

remission or recovery. To support this we found six studies reporting unchanged in vitro measured non-specific T cell proliferation (Albrecht et al. 1985; Schleifer et al. 1989; Wodarz et al. 1991; Andreoli et al. 1992; Hickie et al. 1993; Bauer et al. 1995) (Fig. 2) while 13 studies reported a significant reduction in non-specific T cell proliferation in MDD compared with controls. Although the numbers were small in most studies the results demonstrate a significant relationship between MDD and the measured T cell response.

The Role of T Cell Apoptosis During Adaptive Immune Conditions As with any type of immune activation the function of programmed cell death or apoptosis is also important in mediating adaptive T cell roles during MDD. Apoptosis is an important pathological process as it removes activated T cells that are no longer required thereby ensuring the removal of potentially autoreactive T cells. As a result T cell numbers are always tightly controlled in line with cellular homeostasis. In a case control study in MDD patients, measuring apoptotic lymphocyte activity by staining for the apoptosis facilitating receptor CD95, an increased number of CD95+ cells as well as an increase in the proportion of lymphocytes with nuclear fragmentation was shown in MDD compared to controls

Fig. 2 Schematic model of adaptive and maladaptive T cell mechanisms in depression. Legend: Chronic stress inducing chronic low grade inflammation as found in current MDD leads to an innate immune activation including a dysregulated HPA axis. Included in the initial innate immune responses are activated microglia and astrocytes which release pro-inflammatory cytokines including TNFα and IL-6. With chronic increased levels of cortisol and catelcholamines T cells become glucocorticoid receptor desensitised and unresponsive to cortisol inhibitory effects. The maladaptive T cell responses may also lead to reduced neurogenesis as measured by decreased peripheral neurotrophic growth factor levels from peripheral lymphocytes. Conversely the

maladaptive T cell response may include increased CD4+Th17 proinflammatory T cells with a reduction in Tregs and anti-inflammatory CKs such as IL-10 and TGF-β. During remission of MDD T cell counts remain unchanged and exhibit impaired in vitro proliferative responses to mitogens. While circulating CNS specific T cells are important in resolving the neuroinflammation, increased Fas mediated apoptosis may be beneficial in terms of removing GCR desensitised proliferating T cells. Abbreviations: NK natural killer cells, CK cytokines, BDNF brain derived neurotrophic factor, GCR glucocorticoid receptor, MDD major depressive disorders, CRH corticotropin releasing hormone, ACTH Adrenocorticotropic hormone

(Ivanova et al. 2007). This observation was in parallel to a decrease in CD4+ T cells. Further investigation into the T cell subtypes in a separate study (Szuster-Ciesielska et al. 2008) determined only CD4+, but not CD8+ T cells to have increased CD95 in MDD versus controls. Their findings of accelerated apoptosis within the MDD group should be read with caution including their other findings of increased proapoptotic bax expression and oxidative stress (measured by overproduction of reactive oxygen species (ROS)) as these measurements were made in participants with smoking habits. Smoking is associated with an increased expression of Fas and although both MDD and healthy control groups contained smokers the amount was not standardised. Increased T cell apoptosis may be one of the reasons for the observed decrease in number and responsiveness of T cells as seen during depression (Eilat et al. 1999) and as depicted as an adaptive T cell response in Fig. 2. Increased T cell apoptosis in the context of increased immune activation may be a consequence of tryptophan depletion (Mellor and Munn 2003). Furthermore chronic exposure to pro-inflammatory cytokines such as TNFα and as observed in MDD can promote T cell apoptotic gene dysregulation (Hong et al. 2015).

Effects of Regulatory T Cells, T Cell Inhibitory Regulators and T Cell Differentiation Factors on the Balance Between T Cell Maladaptation and Adaptation in MDD Growing interest lies with regulatory T cells (Tregs), which are able to regulate immunoregulatory processes to maintain a Th1/Th2 cytokine balance (Xu et al. 2003) as well as tolerance to self-antigens (Liu et al. 2006; Sakaguchi et al. 2008). In line with the monoamine theory of depression, MDD is characterised by low levels of 5-hydroxytryptamine (5HT). 5HT is not only a neurotransmitter but also an immune modulator influencing the function of NK, macrophages, pre-B cells and T cells (Ahern 2011). In particular the 5HT receptor subtype 5HTR1aR is associated with peripheral T cell activities. Three studies reported Tregs, as defined by the panel CD4+CD25+Foxp3+, to be decreased in MDD patients and therefore shown to be part of the maladaptive role of T cells in Fig. 2. One study (Li et al. 2010) found diminished Tregs in parallel to an imbalanced Th1/Th2 cytokine ratio with lower levels of 5HT in the plasma and 5HTR1aR mRNA in Tregs of MDD patients when compared with controls suggesting an important role for serotonin in maintaining Treg levels.

Conversely (Himmerich et al. 2010), found 6 weeks of antidepressant treatment in a naturalistic type of study to increase Tregs as well as reduce serum IL-1β levels when compared to prior anti-depressant treatment levels. The precise mechanisms of serotonin mediated T cell modulation during depression remains to be investigated. One study (Chen et al. 2011) explored the relationship between a co-existing autoimmunity within the context of Tregs during MDD. Although MDD patients exhibited a significant decrease in circulating Tregs, a significant increase in the autoimmune inducing Th17 cells was found when compared to controls. Further investigation showed not only an increase in mRNA of the master transcription regulator of Th17 cells, ROR t, but also an increase in serum IL-17 from MDD patients compared to controls. While these studies are setting the premise for an interrelationship between pathogenic Th17 cells and Tregs, the autoimmune processes within MDD remain to be determined. Recent studies in PTSD mouse models also support the notion that Tregs maintain the tight regulation and balance between the risk of pathological autoimmunity and the need for CNS protective autoreactive T cells (Cohen et al. 2007). Depletion of Tregs provides a beneficial environment for CNS reactive T cells to restore brain homeostasis. The exact mechanisms for this remain to be determined but include homing and activation of CNS specific T cells to site of insult followed by modulating the local immune response from resident innate immune cells such as microglia to a defensive phenotype (Schwartz 2003; Shaked et al. 2004). This includes the release of neurotropic factors such as BDNF, vascular endothelial growth factor (VEGF) and insulin-like growth factor (IGF-1) as well as inducing production of such factors from the local microglia and astrocytes. T cell activation and reactivity and thereby T cell tolerance is regulated by the cytotoxic T lymphocyte antigen-4 (CTLA4). CTLA-4 is therefore strong candidate for regulating the balance between adaptive and maladaptive T cell responses in MDD as it regulates T cell function through the apoptotic pathway (Gribben et al. 1995). Two studies reported on the association between CTLA-4 polymorphisms and MDD in two Asian populations. Using single strand conformation polymorphism (SSCP), the authors (Jun et al. 2001) found a significant association between MDD and the exon 1 CTLA-4 gene single nucleotide polymorphism (SNP) rs231775 (A49G) within the Korean and Caucasian population but not the Japanese population or within the Korean population. A larger study (Liu et al. 2011) investigated 6 CTLA-4 SNPs in a Chinese Han population and found that the allele and genotype at rs231779 was significantly associated with MDD as well as bipolar disorder and schizophrenia. Although this SNP is located in an intron, both these studies suggest genetic heterogeneity in this T cell associated locus may confer susceptibility to MDD in certain ethnic populations.

In a Mexican-American cohort, the authors (Wong et al. 2008) reported 2 T cell functional genes to be associated with MDD. Furthermore they found that genetic variation affecting T cell function (TBX21 Tbet T cell differentiation) and HPA axis regulation (PSMB4 proteosome b4 subunit important in antigen processing) was also associated with anti-depressant treatment response. Although a significant association between MDD and polymorphisms in the T cell differentiation regulator were found the authors found no clear Th1 or Th2 cytokine pattern. These findings suggest that T cell dysregulation may be driven by gene x environment interactions and is not solely defined as a consequence of immune mediated responses. These studies do however suggest that T cell specific gene polymorphisms may play a role in risk susceptibility to MDD.

Discussion From the above literature search our current understanding of the roles of T cells in the balance of neuroinflammation, is that a spectrum of functional T cells mediate the balance between pathogenesis and homeostasis of immune cell mediated MDD. This review suggests that peripheral T cells display maladaptive characteristics in a pro-inflammatory MDD environment in in terms of increased CD4+ (and in particular Th17+ cells) concurrent with a decrease in regulatory T cell numbers. The review findings also suggest that T cells may have a maladaptive role in mediating reduced neurogenesis mechanisms as carried out by neuroprotective growth factors Underlying T cell gene polymorphisms can also contribute to chronic neuroinflammation. As the clinical progression of MDD moves into remission T cells become more adaptive as their numbers remain unchanged and their in vitro proliferative status is diminished. Our review findings also suggest that as part of their adaptation to MDD, T cells undergo apoptosis to ensure uncontrolled proliferation is prevented. In contrast, early animal studies have found that an influx of surveilling CNS specific T cells at the choroid plexus are actively participating in regeneration and restoration of damaged neuronal pathways. The review findings also point to a role of regulatory T cells in maintaining this balance. Furthermore underlying T cell gene polymorphismsin epigenetic T cell differentiation regulators carry the capacity to balance between adaptive and maladaptive processes. It is important to remember that neuroinflammatory responses within the CNS are context dependent. This means that responses occurring due to either psychological stress or CNS injury are similar with regard to the participation of activated resident CNS innate immune cells and their secretion of cytokines, chemokines and secondary messengers. However, it is the nature of the inflammatory response being either transient or chronic which delineates whether the

involvement of T cells will become adaptive or maladaptive. In general transient CNS inflammation is beneficial as the immune response adapts to the initial stressor and returns the interconnected systems to homeostasis. Within the CNS resident innate immune cells including astrocytes and microglia as well as peripherally derived monocytes secrete cytokines, chemokines and secondary messengers. In contrast chronic exposure to stress can lead to maladaptive activation of cellular pathways which affect neuronal plasticity and integrity thereby altering brain homeostasis. The long-term presence of pro-inflammatory cytokines can lead to exacerbated neuropathology associated with MDD. As part of the bidirectional neuroimmune communication negative feedback mechanisms via humoral and neuronal pathways provide important checkpoints to modulate the immune response thereby ultimately returning behavioural consequences of neuroinflammation to a healthy state. Although we found no MDD specific literature investigating CNS specific T cells recent animal studies show that as part of the T cell balancing act to maintain immune homeostasis CNS specific T cells which partially cross-react with self Ag such as myelin basic protein (MBP) are continuously carrying out surveillance of the CNS (Baruch and Schwartz 2013). This includes being involved in CNS self-repair activities and maintenance of CNS plasticity including neurogenesis and spatial learning/memory in the normal healthy brain (Kipnis et al. 2004; Ziv et al. 2006; Wolf et al. 2009). During neuroinflammation these circulating CNS specific T cells are required to mitigate stress-induced depressive like behaviour and restore brain homeostasis (Lewitus et al. 2009). By facilitating the recruitment of monocyte-derived macrophages these T cells exhibit beneficial adaptive roles and arrest local microglial toxicity as present during neuroinflammation (Schwartz et al. 2009; London et al. 2011). Neuroinflammation during MDD is generally regarded as being characterised by reduced T cell numbers with an activated phenotype. This review found that the majority of studies reported an unchanged number of lymphocytes in MDD although previous reviews suggest lymphopenia (low numbers of lymphocytes). In studies presenting with lymphopenia this was found to be due to decreased NK cell counts but not T cells. Further in-depth investigations into the meta-analysis from 2001 (Zorrilla et al. 2001) showed a significant negative association for the number of lymphocytes and MDD but only for the fixed and not the random effect. While both measures were reported, the random effects analyses would account for the psychiatric heterogeneity found in MDD. As such this systematic review would support the latter results. However, our review supports this previous meta-analysis (Zorrilla et al. 2001) in other findings of no significant association between CD4+ or CD8+ T cells and MDD as well as a significant association with MDD and higher CD4/CD8 ratio for both fixed and random effect. Similarly in agreement with the

meta-analysis, our review also shows a significant decreased cellular immune response (Zorrilla et al. 2001). This hyporesponsiveness may be due to overproduction of proinflammatory CKs such as TNFα rendering T cells refractory and unable to respond to Ag stimulation (Cope et al. 1997), prostaglandin secretion and the presence of sIL-2Rs which may compete with IL-2 for binding to cellular IL2Rs. Down regulation of immune function may also be due to HPA-axis hyperactivity and lowered available L-tryptophan as found in MDD (Maes et al. 1994b). The majority of T cell functional in vitro studies showed altered mitogen-induced proliferation. Whether this is representative of in vivo T cell mediated immune responses remains debatable. However, impaired DTH responses in vivo in depressed patients have been reported (Hickie et al. 1995). Conversely, other studies assessing wound repair which involves a functioning immune response found that depressed patients exhibit longer wound healing time compared to nondepressed patients (Kiecolt-Glaser et al. 1995; Cole-King and Harding 2001). Ambiguous in vitro T cell proliferation results may exist across MDD studies due to the psychiatrically heterogeneous patient sample. Other limiting factors include methodological limitations coupled with limited sample number as well as including diversity on self-report and clinician rated measures of depression severity. Sub-classifications of MDD into distinct clinical subtypes including minor, simple major and melancholic (Rothermundt et al. 2001) may be useful as different subgroups of MDD may be characterised by different T cell responses. Furthermore, the majority of studies retrieved were cross-sectional, which would exclude measurements of T cell changes at different stages of MDD or only be representative of the T cell response at one particular stage. For example symptom severity of PTSD was found to predict T cell activation in women with childhood maltreatment (Lemieux et al. 2008). It remains to be seen whether the severity of MDD could be a predictor for the type of T cell activation and functionality. What is also not clear from these studies is the degree of T cell activation and polarisation or differentiation. Important in the immunmodulating activities of T cells are also structural interfaces such as the choroid plexus. This area between the CSF and brain are important in immunmodulation by regulating traffic of peripheral leukocytes (Baruch and Schwartz 2013). At this interchange activated and CNS specific CD4+ T cells are found with an effector memory phenotype expressing Th1 and Th2 CKs IFNγ and IL-4 respectively (Kunis et al. 2013) in contrast to the cellular composition of the ventricular and lumbar CSF, which is dominated by CD4+ central memory T cells (Kivisakk et al. 2003; Provencio et al. 2005). As yet the roles of central memory and effector memory T cells in MDD remain to be determined. It would be interesting and clinically relevant to know if they play a role in remitting relapsing depression.

Behavioural interventions including exercise, psychotherapy and ECT tend to not only have anti-depressant effects but also reduce peripheral inflammatory biomarkers. At this stage and from our literature search it is too early to specify which behavioural intervention employs either a detrimental or beneficial T cell role. Already studies investigating mindfulness based therapies including yoga are reporting decreases in proinflammatory cytokines eg IL-6 (Kiecolt-Glaser et al. 2010) as well as influences on gene expression in lymphocytes (Qu et al. 2013). Although speculative it is conceivable that consistent relaxation based practises during MDD can switch on the anti-inflammatory effects of the parasympathetic nervous system as mediated by T cells (O’Mahony et al. 2009) and future studies should be directed at measuring T cell functionality.

assimilating biological data from PBMCs, cerebrospinal fluid (CSF) and post mortem brain tissue with neuroimaging and clinical data. Utilisation of -omics technology including methylation DNA immunoprecipitation (Me-DIP) for epigenetic analyses followed by high throughput next generation sequencing or label free liquid chromatography tandem mass spectrometry (LC/MS/MS) will provide further characterisation of T cell cells, their TCR specificity and ultimately their roles in the bidirectional neuroimmune communication. Further comprehensive immunoassays including advanced flow cytometric analyses of simultaneous intracellular and cell surface markers and multiplex immunoassays for identification of immune cell signalling molecules will provide a more detailed platform on which to design panels of depression specific biomarkers and individualised therapeutic strategies.

Future Directions Although more evidence suggests that autoreactive T cells are important in ‘protective autoimmunity’ (Schwartz and Baruch 2014), their specificity in MDD patients remains to be determined. Further high throughput sequencing of the T cell receptor (TCR) repertoire would be able to identify CNS specificity (Baruch and Schwartz 2013). Other key regulators of T cells include those at the gene level such as epigenetic regulators including histone deacetylases (HDACs). These have recently been shown to be involved in brain function (Volmar et al. 2015) and mood disorders (Hobara et al. 2010) as seen in, their ability to enhance Tregs neuroinflammation after ischemia (Liesz et al. 2013). Other key regulators of T cell differentiation include the transcription factor Tbet. This master regulator of Th1 cells has been found to be the quantitative regulator of IFNγ secretion in a study using single cell analyses and mathematical modelling (Helmstetter et al. 2015). The authors further propose that ‘quantitative cytokine memory’ is regulated at multiple regulatory sites including epigenetic modifications and interactions between Tbet and NF-kB family members. Technological advancement such as in the realm of gene analyses has enabled T cell specific gene polymorphisms to be defined. Similarly continued development of specific monoclonal antibodies against T cell surface markers as well as other cells of the neuroendocrine and neuroimmune systems has enabled better definition of T cell roles within these pathways. In spite of this recent studies have not for example extended the use of multicolour and intracellular flow cytometry panels to delineate the different T cell subsets eg Th1, Th2 or Th17, which would not only facilitate phenotypic identification of the effector T cells involved in MDD but also simultaneous functional capacity. Future mechanistic studies into the precise roles of T cells during depression will require multi-centre and interdisciplinary approaches using carefully designed studies. This will include research and biobank centres collaborating and

Conclusion T cells have pivotal roles to play in depression. Their interaction with resident CNS innate immune cells and other peripherally derived immune cells as well as the neuroendocrine system determine the inflammatory profiles as found in some MDD subtypes. While it is now understood that some T cell mechanisms if prolonged can become maladaptive leading to neurodegeneration and altered brain physiology it is now also recognised that adaptive T cell mechanisms can be beneficial and lead to neurorepair and protection. T cell phenotypes and responses are most likely part of a continuum in which T cell plasticity and fluidity is paramount in maintaining immune homeostasis. While clinicians are looking to correlate MDD associated risk factors with panels of certain immune markers using -omics based platforms and pathway analyses what remains is deciphering the actual T cell biology. With a more multicantered approach to MDD cohorts and a more constructive characterisation of T cell functionality this should be possible. In the future, MDD therapies will not globally manipulate the immune response, but rather immunmodulate targeted key effector cells. Even better would be to harness the inherent inflammation resolving mechanisms to promote a return to homeostasis and thereby clinical remission of MDD. Perhaps therapies including mindfulness-based therapies such as psychotherapy or yoga which have the potential to reactivate these mechanisms as they return the body and mind to a relaxed state. Further functional T cell knowledge may also enable restoration and regeneration of CNS affected areas as seen in MDD. Acknowledgments The authors wish to acknowledge Evan Papavasiliou, Dhiren Dhanji, and Felicity Watson for their assistance in the literature search and Gaurav Singhal for assistance in formatting Fig. 2. This work is supported by the James and Diana Ramsay Foundation, South Australia, Australia. Conflict of Interest The authors have no conflicts of interest to declare.

References Ader R (1981) Animal models in the study of brain, behavior and bodily disease. Res Publ Assoc Res Nerv Ment Dis 59:11–26 Ahern GP (2011) 5-HT and the immune system. Curr Opin Pharmacol 11: 29–33 Albrecht J, Helderman JH, Schlesser MA, Rush AJ (1985) A controlled study of cellular immune function in affective disorders before and during somatic therapy. Psychiatry Res 15:185–193 Altshuler LL, Plaeger-Marshall S, Richeimer S, Daniels M, Baxter LR Jr (1989) Lymphocyte function in major depression. Acta Psychiatr Scand 80:132–136 Andreoli A, Keller SE, Rabaeus M, Zaugg L, Garrone G, Taban C (1992) Immunity, major depression, and panic disorder comorbidity. Biol Psychiatry 31:896–908 Anforth HR, Bluthe RM, Bristow A, Hopkins S, Lenczowski MJ, Luheshi G, Lundkvist J, Michaud B, Mistry Y, Van Dam AM, Zhen C, Dantzer R, Poole S, Rothwell NJ, Tilders FJ, Wollman EE (1998) Biological activity and brain actions of recombinant rat interleukin-1alpha and interleukin-1beta. Eur Cytokine Netw 9: 279–288 Anesi A, Franciotta D, Di Paolo E, Zardini E, Melzi d'Eril GV, Zerbi F (1994) PHA-stimulated cellular immune function and T-lymphocyte subsets in major depressive disorders. Funct Neurol 9:17–22 Baruch K, Schwartz M (2013) CNS-specific T cells shape brain function via the choroid plexus. Brain Behav Immun 34:11–16 Bauer ME, Gauer GJ, Luz C, Silveira RO, Nardi NB, von Muhlen CA (1995) Evaluation of immune parameters in depressed patients. Life Sci 57:665–674 Berard M, Tough DF (2002) Qualitative differences between naive and memory T cells. Immunology 106:127–138 Beurel E, Harrington LE, Jope RS (2013) Inflammatory T helper 17 cells promote depression-like behavior in mice. Biol Psychiatry 73:622– 630 Blalock JE, Smith EM (2007) Conceptual development of the immune system as a sixth sense. Brain Behav Immun 21:23–33 Bluthe RM, Laye S, Michaud B, Combe C, Dantzer R, Parnet P (2000) Role of interleukin-1beta and tumour necrosis factor-alpha in lipopolysaccharide-induced sickness behaviour: a study with interleukin-1 type I receptor-deficient mice. Eur J Neurosci 12: 4447–4456 Bromet E et al (2011) Cross-national epidemiology of DSM-IV major depressive episode. BMC Med 9:90 Capuron L, Dantzer R (2003) Cytokines and depression: the need for a new paradigm. Brain Behav Immun 17(Suppl 1):S119–S124 Carson MJ, Doose JM, Melchior B, Schmid CD, Ploix CC (2006) CNS immune privilege: hiding in plain sight. Immunol Rev 213:48–65 Chen Y, Jiang T, Chen P, Ouyang J, Xu G, Zeng Z, Sun Y (2011) Emerging tendency towards autoimmune process in major depressive patients: a novel insight from Th17 cells. Psychiatry Res 188: 224–230 Cohen H, Kaplan Z, Matar MA, Loewenthal U, Zohar J, Richter-Levin G (2007) Long-lasting behavioral effects of juvenile trauma in an animal model of PTSD associated with a failure of the autonomic nervous system to recover. Eur Neuropsychopharmacol J Eur Coll Neuropsychopharmacol 17:464–477 Cole-King A, Harding KG (2001) Psychological factors and delayed healing in chronic wounds. Psychosom Med 63:216–220 Cope A, Ettinger R, McDevitt H (1997) The role of TNF alpha and related cytokines in the development and function of the autoreactive T-cell repertoire. Res Immunol 148:307–312 Dantzer R (2001) Cytokine-induced sickness behavior: where do we stand? Brain Behav Immun 15:7–24

Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW (2008) From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 9:46–56 Darko DF, Gillin JC, Risch SC, Bulloch K, Golshan S, Tasevska Z, Hamburger RN (1989) Mitogen-stimulated lymphocyte proliferation and pituitary hormones in major depression. Biol Psychiatry 26:145–155 Darko DF et al (1988) Cellular immunity and the hypothalamic-pituitary axis in major affective disorder: a preliminary study. Psychiatry Res 25:1–9 DellaGioia N, Hannestad J (2010) A critical review of human endotoxin administration as an experimental paradigm of depression. Neurosci Biobehav Rev 34:130–143 Denicoff KD, Rubinow DR, Papa MZ, Simpson C, Seipp CA, Lotze MT, Chang AE, Rosenstein D, Rosenberg SA (1987) The neuropsychiatric effects of treatment with interleukin-2 and lymphokineactivated killer cells. Ann Intern Med 107:293–300 Dhabhar FS (2008) Enhancing versus suppressive effects of stress on immune function: implications for immunoprotection versus immunopathology. Allergy Asthma Clin Immunol Off J Can Soc Allergy Clin Immunol 4:2–11 Dickens C, McGowan L, Clark-Carter D, Creed F (2002) Depression in rheumatoid arthritis: a systematic review of the literature with metaanalysis. Psychosom Med 64:52–60 Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, Lanctot KL (2010) A meta-analysis of cytokines in major depression. Biol Psychiatry 67:446–457 Dunn AJ, Swiergiel AH, de Beaurepaire R (2005) Cytokines as mediators of depression: what can we learn from animal studies? Neurosci Biobehav Rev 29:891–909 Eilat E, Mendlovic S, Doron A, Zakuth V, Spirer Z (1999) Increased apoptosis in patients with major depression: a preliminary study. J Immunol 163:533–534 Elgun S, Keskinege A, Kumbasar H (1999) Dipeptidyl peptidase IV and adenosine deaminase activity. Decrease in depression. Psychoneuroendocrinology 24:823–832 Farid Hosseini R et al (2007) Assessment of the immune system activity in Iranian patients with Major Depression Disorder (MDD). Iran J Immunol : IJI 4:38–43 Fitzgerald P, O’Brien SM, Scully P, Rijkers K, Scott LV, Dinan TG (2006) Cutaneous glucocorticoid receptor sensitivity and pro-inflammatory cytokine levels in antidepressant-resistant depression. Psychol Med 36:37–43 Galea I, Bechmann I, Perry VH (2007) What is immune privilege (not)? Trends Immunol 28:12–18 Greden JF (2001) The burden of disease for treatment-resistant depression. J Clin Psychiatry 62(Suppl 16):26–31 Gribben JG, Freeman GJ, Boussiotis VA, Rennert P, Jellis CL, Greenfield E, Barber M, Restivo VA Jr, Ke X, Gray GS et al (1995) CTLA4 mediates antigen-specific apoptosis of human T cells. Proc Natl Acad Sci U S A 92:811–815 Haroon E, Raison CL, Miller AH (2012) Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol 37:137–162 Harrison NA, Brydon L, Walker C, Gray MA, Steptoe A, Critchley HD (2009) Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity. Biol Psychiatry 66:407–414 Hart BL (1988) Biological basis of the behavior of sick animals. Neurosci Biobehav Rev 12:123–137 Helmstetter C, Flossdorf M, Peine M, Kupz A, Zhu J, Hegazy AN, Duque-Correa MA, Zhang Q, Vainshtein Y, Radbruch A, Kaufmann SH, Paul WE, Hofer T, Lohning M (2015) Individual T helper cells have a quantitative cytokine memory. Immunity 42: 108–122

Herbert TB, Cohen S (1993) Depression and immunity: a meta-analytic review. Psychol Bull 113:472–486 Hickie I, Hickie C, Lloyd A, Silove D, Wakefield D (1993) Impaired in vivo immune responses in patients with melancholia. Br J Psychiatry J Ment Sci 162:651–657 Hickie I, Hickie C, Bennett B, Wakefield D, Silove D, Mitchell P, Lloyd A (1995) Biochemical correlates of in vivo cell-mediated immune dysfunction in patients with depression: a preliminary report. Int J Immunopharmacol 17:685–690 Himmerich H, Milenovic S, Fulda S, Plumakers B, Sheldrick AJ, Michel TM, Kircher T, Rink L (2010) Regulatory T cells increased while IL1beta decreased during antidepressant therapy. J Psychiatr Res 44: 1052–1057 Hobara T, Uchida S, Otsuki K, Matsubara T, Funato H, Matsuo K, Suetsugi M, Watanabe Y (2010) Altered gene expression of histone deacetylases in mood disorder patients. J Psychiatr Res 44:263–270 Hong M, Zheng J, Ding ZY, Chen JH, Yu L, Niu Y, Hua YQ, Wang LL (2013) Imbalance between Th17 and Treg cells may play an important role in the development of chronic unpredictable mild stressinduced depression in mice. Neuroimmunomodulation 20:39–50 Hong S, Kim EJ, Lee EJ, San Koo B, Min Ahn S, Bae SH, Lim DH, Kim YG, Yoo B, Lee CK (2015) TNF-alpha confers resistance to Fasmediated apoptosis in rheumatoid arthritis through the induction of soluble Fas. Life Sci 122:37–41 McAdams C, Leonard BE (1993) Neutrophil and monocyte phagocytosis in depressed patients. Prog Neuro-Psychopharmacol Biol Psychiatry 17:971–984 Irwin M, Daniels M, Bloom ET, Smith TL, Weiner H (1987) Life events, depressive symptoms, and immune function. Am J Psychiatry 144: 437–441 Ivanova S, Semke V, Vetlugina T, Rakitina N, Kudyakova T, Simutkin G (2007) Signs of apoptosis of immunocompetent cells in patients with depression. Neurosci Behav Physiol 37:527–530 Janszky I, Lekander M, Blom M, Georgiades A, Ahnve S (2005) Selfrated health and vital exhaustion, but not depression, is related to inflammation in women with coronary heart disease. Brain Behav Immun 19:555–563 Jun TY, Pae CU, Chae JH, Bahk WM, Kim KS (2001) Polymorphism of CTLA-4 gene for major depression in the Korean population. Psychiatry Clin Neurosci 55:533–537 Karabatsiakis A, Kolassa IT, Kolassa S, Rudolph KL, Dietrich DE (2014) Telomere shortening in leukocyte subpopulations in depression. BMC Psychiatry 14:192 Kaster MP, Gadotti VM, Calixto JB, Santos AR, Rodrigues AL (2012) Depressive-like behavior induced by tumor necrosis factor-alpha in mice. Neuropharmacology 62:419–426 Kiecolt-Glaser JK, Marucha PT, Malarkey WB, Mercado AM, Glaser R (1995) Slowing of wound healing by psychological stress. Lancet 346:1194–1196 Kiecolt-Glaser JK, Christian L, Preston H, Houts CR, Malarkey WB, Emery CF, Glaser R (2010) Stress, inflammation, and yoga practice. Psychosom Med 72:113–121 Kipnis J, Cohen H, Cardon M, Ziv Y, Schwartz M (2004) T cell deficiency leads to cognitive dysfunction: implications for therapeutic vaccination for schizophrenia and other psychiatric conditions. Proc Natl Acad Sci U S A 101:8180–8185 Kivisakk P, Mahad DJ, Callahan MK, Trebst C, Tucky B, Wei T, Wu L, Baekkevold ES, Lassmann H, Staugaitis SM, Campbell JJ, Ransohoff RM (2003) Human cerebrospinal fluid central memory CD4+ T cells: evidence for trafficking through choroid plexus and meninges via P-selectin. Proc Natl Acad Sci U S A 100:8389–8394 Klegeris A, Schulzer M, Harper DG, McGeer PL (2007) Increase in core body temperature of Alzheimer’s disease patients as a possible indicator of chronic neuroinflammation: a meta-analysis. Gerontology 53:7–11

Kowal SJ (1955) Emotions as a cause of cancer; 18th and 19th century contributions. Psychoanal Rev 42:217–227 Kronfol Z, House JD (1984) Depression, cortisol, and immune function. Lancet 1:1026–1027 Kronfol Z, House J (1989) Lymphocyte, mitogenesis, immunoglobulin and complement levels in depressed patients and normal controls. Acta Psychiatr Scand 80:142–147 Kronfol Z, House JD, Silva J Jr, Greden J, Carroll BJ (1986) Depression, urinary free cortisol excretion and lymphocyte function. Br J Psychiatry J Ment Sci 148:70–73 Kronfol Z, Silva J Jr, Greden J, Dembinski S, Gardner R, Carroll B (1983) Impaired lymphocyte function in depressive illness. Life Sci 33: 241–247 Kunis G, Baruch K, Rosenzweig N, Kertser A, Miller O, Berkutzki T, Schwartz M (2013) IFN-gamma-dependent activation of the brain’s choroid plexus for CNS immune surveillance and repair. Brain J Neurol 136:3427–3440 Lanquillon S, Krieg JC, Bening-Abu-Shach U, Vedder H (2000) Cytokine production and treatment response in major depressive d i s o r d e r. N e u r o p s y c h o p h a r m a c o l O ff P u b l A m C o l l Neuropsychopharmacol 22:370–379 Lemieux A, Coe CL, Carnes M (2008) Symptom severity predicts degree of T cell activation in adult women following childhood maltreatment. Brain Behav Immun 22:994–1003 Leonard B, Maes M (2012) Mechanistic explanations how cell-mediated immune activation, inflammation and oxidative and nitrosative stress pathways and their sequels and concomitants play a role in the pathophysiology of unipolar depression. Neurosci Biobehav Rev 36:764–785 Leonard RC, North NT, Whelan JM (1987) Talking about cancer. Br J Hosp Med 38:579 Levy EM et al (1991) Biological measures and cellular immunological function in depressed psychiatric inpatients. Psychiatry Res 36:157– 167 Lewitus GM, Wilf-Yarkoni A, Ziv Y, Shabat-Simon M, Gersner R, Zangen A, Schwartz M (2009) Vaccination as a novel approach for treating depressive behavior. Biol Psychiatry 65:283–288 Li Y, Xiao B, Qiu W, Yang L, Hu B, Tian X, Yang H (2010) Altered expression of CD4(+)CD25(+) regulatory T cells and its 5-HT(1a) receptor in patients with major depression disorder. J Affect Disord 124:68–75 Liesz A, Zhou W, Na SY, Hammerling GJ, Garbi N, Karcher S, Mracsko E, Backs J, Rivest S, Veltkamp R (2013) Boosting regulatory T cells limits neuroinflammation in permanent cortical stroke. J Neurosci Off J Soc Neurosci 33:17350–17362 Liu W, Putnam AL, Xu-Yu Z, Szot GL, Lee MR, Zhu S, Gottlieb PA, Kapranov P, Gingeras TR, de St F, Groth B, Clayberger C, Soper DM, Ziegler SF, Bluestone JA (2006) CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med 203:1701–1711 Liu J, Li J, Li T, Wang T, Li Y, Zeng Z, Li Z, Chen P, Hu Z, Zheng L, Ji J, Lin H, Feng G, Shi Y (2011) CTLA-4 confers a risk of recurrent schizophrenia, major depressive disorder and bipolar disorder in the Chinese Han Population. Brain Behav Immun 25:429–433 London A, Itskovich E, Benhar I, Kalchenko V, Mack M, Jung S, Schwartz M (2011) Neuroprotection and progenitor cell renewal in the injured adult murine retina requires healing monocyte-derived macrophages. J Exp Med 208:23–39 Lopez AD, Mathers CD (2006) Measuring the global burden of disease and epidemiological transitions: 2002–2030. Ann Trop Med Parasitol 100:481–499 Lukic I, Mitic M, Djordjevic J, Tatalovic N, Bozovic N, Soldatovic I, Mihaljevic M, Pavlovic Z, Radojcic MB, Maric NP, Adzic M (2014) Lymphocyte levels of redox-sensitive transcription factors and antioxidative enzymes as indicators of pro-oxidative state in depressive patients. Neuropsychobiology 70:1–9

Maes M, Bosmans E, Suy E, Minner B, Raus J (1989) Immune cell parameters in severely depressed patients: negative findings. J Affect Disord 17:121–128 Maes M, Bosmans E, Suy E, Vandervorst C, DeJonckheere C, Raus J (1991) Depression-related disturbances in mitogen-induced lymphocyte responses and interleukin-1 beta and soluble interleukin-2 receptor production. Acta Psychiatr Scand 84:379–386 Maes M, Stevens W, DeClerck L, Bridts C, Peeters D, Schotte C, Cosyns P (1992a) Immune disorders in depression: higher T helper/T suppressor-cytotoxic cell ratio. Acta Psychiatr Scand 86:423–431 Maes M, Lambrechts IJ, Bosmans E, Jacobs J, Suy E, Vandervorst C, De Jonckheere C, Minner B, Raus J (1992b) Evidence for a systemic immune activation during depression: results of leukocyte enumeration by flow cytometry in conjunction with monoclonal antibody staining. Psychol Med 22:45–53 Maes M, Scharpe S, Bosmans E, Vandewoude M, Suy E, Uyttenbroeck W, Cooreman W, Vandervorst C, Raus J (1992c) Disturbances in acute phase plasma proteins during melancholia: additional evidence for the presence of an inflammatory process during that illness. Prog Neuro-Psychopharmacol Biol Psychiatry 16:501–515 Maes M, Stevens WJ, Declerck LS, Bridts CH, Peters D, Schotte C, Cosyns P (1993) Significantly increased expression of T-cell activation markers (interleukin-2 and HLA-DR) in depression: Further evidence for an inflammatory process during that illness. Prog Neuro-Psychopharmacol Biol Psychiatry 17:241–255 Maes M, Meltzer HY, Stevens W, Calabrese J, Cosyns P (1994a) Natural killer cell activity in major depression: relation to circulating natural killer cells, cellular indices of the immune response, and depressive phenomenology. Prog Neuro-Psychopharmacol Biol Psychiatry 18: 717–730 Maes M, Scharpe S, Meltzer HY, Okayli G, Bosmans E, D’Hondt P, Vanden Bossche BV, Cosyns P (1994b) Increased neopterin and interferon-gamma secretion and lower availability of L-tryptophan in major depression: further evidence for an immune response. Psychiatry Res 54:143–160 Maes M, Berk M, Goehler L, Song C, Anderson G, Galecki P, Leonard B (2012) Depression and sickness behavior are Janus-faced responses to shared inflammatory pathways. BMC Med 10:66 Maier SF, Watkins LR (1998) Cytokines for psychologists: implications of bidirectional immune-to-brain communication for understanding behavior, mood, and cognition. Psychol Rev 105:83–107 Marazziti D et al (1992) Immune cell imbalance in major depressive and panic disorders. Neuropsychobiology 26:23–26 Mellor AL, Munn DH (2003) Tryptophan catabolism and regulation of adaptive immunity. J Immunol 170:5809–5813 Miller AH (2010) Depression and immunity: a role for T cells? Brain Behav Immun 24:1–8 Minden SL, Schiffer RB (1990) Affective disorders in multiple sclerosis. Review and recommendations for clinical research. Arch Neurol 47: 98–104 Motivala SJ, Sarfatti A, Olmos L, Irwin MR (2005) Inflammatory markers and sleep disturbance in major depression. Psychosom Med 67:187–194 Muller N, Hofschuster E, Ackenheil M, Mempel W, Eckstein R (1993) Investigations of the cellular immunity during depression and the free interval: evidence for an immune activation in affective psychosis. Prog Neuro-Psychopharmacol Biol Psychiatry 17:713–730 Nunes SO et al (2002) Immune and hormonal activity in adults suffering from depression. Braz J Med Biol Res = Rev Bras Pesqui Med Biol / Soc Bras Biofis [et al] 35:581–587 O’Brien SM, Scully P, Fitzgerald P, Scott LV, Dinan TG (2007) Plasma cytokine profiles in depressed patients who fail to respond to selective serotonin reuptake inhibitor therapy. J Psychiatr Res 41:326– 331 O’Mahony C, van der Kleij H, Bienenstock J, Shanahan F, O’Mahony L (2009) Loss of vagal anti-inflammatory effect: in vivo visualization

and adoptive transfer. Am J Physiol Regul Integr Comp Physiol 297: R1118–R1126 Ohara T, Koyama K, Kusunoki Y, Hayashi T, Tsuyama N, Kubo Y, Kyoizumi S (2002) Memory functions and death proneness in three CD4+CD45RO+ human T cell subsets. J Immunol 169:39–48 Pandey GN, Dwivedi Y, Rizavi HS, Ren X, Zhang H, Pavuluri MN (2010) Brain-derived neurotrophic factor gene and protein expression in pediatric and adult depressed subjects. Prog NeuroPsychopharmacol Biol Psychiatry 34:645–651 Pavon L et al (2006) Th2 cytokine response in Major Depressive Disorder patients before treatment. J Neuroimmunol 172:156–165. doi:10. 1016/j.jneuroim.2005.08.014 Perini GI et al (1995) Psychoimmunoendocrine aspects of panic disorder. Hum Psychopharmacol Clin Exp 10:461–465. doi:10.1002/hup. 470100605 Provencio JJ, Kivisakk P, Tucky BH, Luciano MG, Ransohoff RM (2005) Comparison of ventricular and lumbar cerebrospinal fluid T cells in non-inflammatory neurological disorder (NIND) patients. J Neuroimmunol 163:179–184 Qu S, Olafsrud SM, Meza-Zepeda LA, Saatcioglu F (2013) Rapid gene expression changes in peripheral blood lymphocytes upon practice of a comprehensive yoga program. PLoS One 8:e61910 Ravindran AV, Griffiths J, Merali Z, Anisman H (1998) Circulating lymphocyte subsets in major depression and dysthymia with typical or atypical features. Psychosom Med 60:283–289 Reddy MS (2010) Depression: the disorder and the burden. Indian J Psychol Med 32:1–2 Renault PF, Hoofnagle JH, Park Y, Mullen KD, Peters M, Jones DB, Rustgi V, Jones EA (1987) Psychiatric complications of long-term interferon alfa therapy. Arch Intern Med 147:1577–1580 Rothermundt M, Arolt V, Fenker J, Gutbrodt H, Peters M, Kirchner H (2001) Different immune patterns in melancholic and nonmelancholic major depression. Eur Arch Psychiatry Clin Neurosci 251:90–97 Rush AJ (2007) STAR*D: what have we learned? Am J Psychiatry 164: 201–204 Sakaguchi S, Yamaguchi T, Nomura T, Ono M (2008) Regulatory T cells and immune tolerance. Cell 133:775–787 Schleifer SJ, Keller SE, Bond RN, Cohen J, Stein M (1989) Major depressive disorder and immunity. Role of age, sex, severity, and hospitalization. Arch Gen Psychiatry 46:81–87 Schleifer SJ, Keller SE, Meyerson AT, Raskin MJ, Davis KL, Stein M (1984) Lymphocyte function in major depressive disorder. Arch Gen Psychiatry 41:484–486 Schwartz M (2003) Macrophages and microglia in central nervous system injury: are they helpful or harmful? J Cereb Blood Flow Metab Off J Int Soc Cerebr Blood Flow Metab 23:385–394 Schwartz M, Baruch K (2014) Breaking peripheral immune tolerance to CNS antigens in neurodegenerative diseases: boosting autoimmunity to fight-off chronic neuroinflammation. J Autoimmun 54:8–14 Schwartz M, Kipnis J (2011) A conceptual revolution in the relationships between the brain and immunity. Brain Behav Immun 25:817–819 Schwartz M, London A, Shechter R (2009) Boosting T-cell immunity as a therapeutic approach for neurodegenerative conditions: the role of innate immunity. Neuroscience 158:1133–1142 Seidel A, Arolt V, Hunstiger M, Rink L, Behnisch A, Kirchner H (1996) Major depressive disorder is associated with elevated monocyte counts. Acta Psychiatr Scand 94:198–204 Shaked I, Porat Z, Gersner R, Kipnis J, Schwartz M (2004) Early activation of microglia as antigen-presenting cells correlates with T cellmediated protection and repair of the injured central nervous system. J Neuroimmunol 146:84–93 Simon NM, Walton Z, Prescott J, Hoge E, Keshaviah A, Bui THE, Schwarz N, Dryman T, Ojserkis RA, Mischoulon D, Worthington J, DeVivo I, Fava M, Wong KK (2013) A cross-sectional examination of telomere length and telomerase in a well-characterized

sample of individuals with major depressive disorder compared to c o n t r o l s . N e u r o p s y c h o p h a r m a c o l O ff P u b l A m C o l l Neuropsychopharmacol 38:S322–S323 Sluzewska A, Sobieska M, Rybakowski JK (1997) Changes in acutephase proteins during lithium potentiation of antidepressants in refractory depression. Neuropsychobiology 35:123–127 Smith RS (1991) The macrophage theory of depression. Med Hypotheses 35:298–306 Solomon GF, Moss RH (1964) Emotions, immunity, and disease; a speculative theoretical integration. Arch Gen Psychiatry 11:657–674 Spurrell MT, Creed FH (1993) Lymphocyte response in depressed patients and subjects anticipating bereavement. Br J Psychiatry J Ment Sci 162:60–64 Stepanichev M, Dygalo NN, Grigoryan G, Shishkina GT, Gulyaeva N (2014) Rodent models of depression: neurotrophic and neuroinflammatory biomarkers. BioMed Res Int 2014:932757 Suzuki K, Iwata Y, Matsuzaki H, Anitha A, Suda S, Iwata K, Shinmura C, Kameno Y, Tsuchiya KJ, Nakamura K, Takei N, Mori N (2010) Reduced expression of apolipoprotein E receptor type 2 in peripheral blood lymphocytes from patients with major depressive disorder. Prog Neuro-Psychopharmacol Biol Psychiatry 34:1007–1010 Szuster-Ciesielska A, Slotwinska M, Stachura A, MarmurowskaMichalowska H, Dubas-Slemp H, Bojarska-Junak A, KandeferSzerszen M (2008) Accelerated apoptosis of blood leukocytes and oxidative stress in blood of patients with major depression. Prog Neuro-Psychopharmacol Biol Psychiatry 32:686–694 Tian L, Rauvala H, Gahmberg CG (2009) Neuronal regulation of immune responses in the central nervous system. Trends Immunol 30:91–99 Tian L, Ma L, Kaarela T, Li Z (2012) Neuroimmune crosstalk in the central nervous system and its significance for neurological diseases. J Neuroinflammation 9:155 Trivedi MH, Fava M, Wisniewski SR, Thase ME, Quitkin F, Warden D, Ritz L, Nierenberg AA, Lebowitz BD, Biggs MM, Luther JF, Shores-Wilson K, Rush AJ, Team SDS (2006) Medication augmentation after the failure of SSRIs for depression. N Engl J Med 354: 1243–1252 Udina M, Castellvi P, Moreno-Espana J, Navines R, Valdes M, Forns X, Langohr K, Sola R, Vieta E, Martin-Santos R (2012) Interferon-

induced depression in chronic hepatitis C: a systematic review and meta-analysis. J Clin Psychiatry 73:1128–1138 Ustun TB, Ayuso-Mateos JL, Chatterji S, Mathers C, Murray CJ (2004) Global burden of depressive disorders in the year 2000. Br J Psychiatry J Ment Sci 184:386–392 Volmar KE, Idowu MO, Souers RJ, Karcher DS, Nakhleh RE (2015) Turnaround time for large or complex specimens in surgical pathology: a college of american pathologists q-probes study of 56 institutions. Arch Pathol Lab Med 139:171–177 Wodarz N, Rupprecht R, Kornhuber J, Schmitz B, Wild K, Braner H, Riederer P (1991) Normal lymphocyte responsiveness to lectins but impaired sensitivity to in vitro glucocorticoids in major depression. J Affect Disord 22:241–248 Wolf SA, Steiner B, Wengner A, Lipp M, Kammertoens T, Kempermann G (2009) Adaptive peripheral immune response increases proliferation of neural precursor cells in the adult hippocampus. FASEB J Off Publ Fed Am Soc Exp Biol 23:3121–3128 Wong M, Dong C, Maestre-Mesa J, Licinio J (2008) Polymorphisms in inflammation-related genes are associated with susceptibility to major depression and antidepressant response. Mol Psychiatry 13:800– 812 Xu D, Liu H, Komai-Koma M, Campbell C, McSharry C, Alexander J, Liew FY (2003) CD4+CD25+ regulatory T cells suppress differentiation and functions of Th1 and Th2 cells, Leishmania major infection, and colitis in mice. J Immunol 170:394–399 Yu BH, Dimsdale JE, Mills PJ (1999) Psychological states and lymphocyte beta-adrenergic receptor responsiveness. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol 21:147–152 Ziv Y, Schwartz M (2008) Immune-based regulation of adult neurogenesis: implications for learning and memory. Brain Behav Immun 22:167–176 Ziv Y, Ron N, Butovsky O, Landa G, Sudai E, Greenberg N, Cohen H, Kipnis J, Schwartz M (2006) Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat Neurosci 9:268–275 Zorrilla EP, Luborsky L, McKay JR, Rosenthal R, Houldin A, Tax A, McCorkle R, Seligman DA, Schmidt K (2001) The relationship of depression and stressors to immunological assays: a meta-analytic review. Brain Behav Immun 15:199–226