EXG-09315; No of Pages 6 Experimental Gerontology xxx (2014) xxx–xxx

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Role of dendritic cells in innate and adaptive immune response in human aging Sudhir Gupta ⁎ Programs in Primary Immunodeficiency and Human Aging, Division of Basic and Clinical Immunology, University of California, Irvine, CA 92660, USA

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Article history: Received 17 September 2013 Received in revised form 11 December 2013 Accepted 16 December 2013 Available online xxxx Section Editor: Daniela Frasca

a b s t r a c t Aging is associated with a progressive decline in T cell function, chronic inflammation, hyperimmunoglobulinemia, autoimmunity, poor response to vaccines, and increased susceptibility to infection as well as diseases associated with chronic inflammation. DCs in aging appear to be functionally impaired with regard to response to uptake of antigens, phagocytosis of apoptotic cells, migration, priming of CD4+ and CD8+ T cells, and production of IFN-I and IFN-III. In this review I have discussed various mechanisms, which may be responsible for impaired functions of DCs. © 2014 Elsevier Inc. All rights reserved.

Keywords: IFN-I IFN-III NF-κB T cell priming mDC pDC

1. Introduction Dendritic cells are a heterogeneous population of hematopoietic antigen-presenting cells. They play a major role in the innate immune response, in shaping and determining the tempo of the adaptive immune response, and in the maintenance of immunological tolerance, therefore serving as a major link between innate and adaptive immunity (Banchereau et al., 2000; Miriam and Manz, 2009; Ueno et al., 2010). There are two major subpopulations of DCs, namely “conventional” (cDCs), which are also known as myeloid DCs, and plasmacytoid DCs (pDCs). The cDCs are known to differentiate from the common myeloid hematopoietic lineage precursors. Though both pDCs and cDCs can be derived from a common hematopoietic precursor, the relationship between pDCs and cDCs remains controversial (Fitzgerald-Bocarsly et al., 2008). It appears that there is a significant plasticity in the DC lineage. pDCs could be derived from either myeloid or lymphoid precursors (Shigemetssu et al., 2004). Furthermore, pDCs and cDCs maintain plasticity even after their differentiation (Diebold et al., 2003). Therefore, a number of functions are shared between two subtypes of DCs; for example, the production of IFN-I and IFN-III, albeit their relative

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concentrations may be different among two DC subtypes, and priming of naïve T cells. The cDCs exist in peripheral tissues, secondary lymphoid organs, and in the circulating blood. pDCs circulate in the blood and enter lymphoid organs through high endothelial venules. Compared to cDCs, pDCs express different sets of Toll like receptors (TLRs) (Akira et al., 2006). pDCs express TLR7 and TLR9 and upon stimulation secrete large amounts of IFN-α (Siegal et al., 1999). In response to microbial infection, monocytes migrate into inflammatory sites and differentiate into DCs (Siegal et al., 1999). The most common model to study cDCs in humans is in vitro monocyte-derived dendritic cells; in vitro monocytes upon activation with GM-CSF and IL-4 differentiate into monocytederived DCs. In this review I will refer them as mDCs. Aging represents a paradoxical state of immunodeficiency, inflammation and autoimmunity (Bruunsgaard et al., 2001; Fagiola et al., 1993; Franceschi et al., 1995; Gupta et al., 2006; Manavalan et al., 1998; Pawlec et al., 2002; Rink and Kirchner, 1998; Rowley et al., 1968; Tomer and Shoenfeld, 1988; Weksler and Goodhardt, 2002). The progressive impairment in immune functions include progressive T cell deficiency, which is due in part by thymic involution (Rezzani et al., 2014), increased apoptosis of naïve and central memory T cells (Gupta, 2000, 2005; Gupta et al., 2006), and impaired priming of T cells by DCs (Sridharan et al., 2010; Yu et al., 2013, discussed below), and B cell dysfunctions as revealed by impaired specific antibody response to vaccines, autoimmunity, and hyperimmunoglobulinemia (Franceschi et al., 1995; Manavalan et al., 1998; Rowley et al., 1968; Tomer and Shoenfeld, 1988; Weksler and Goodhardt, 2002).

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Please cite this article as: Gupta, S., Role of dendritic cells in innate and adaptive immune response in human aging, Exp. Gerontol. (2014), http:// dx.doi.org/10.1016/j.exger.2013.12.009

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2. Role of DCs in inflammation in aging 2.1. Numbers and morphology of DCs and their differentiation and maturation Several studies have reported age-related changes in the number and functions of DCs in aging. We (Agrawal et al., 2007), and others (Jing et al., 2009; Lung et al., 2000; Steger et al., 1996) have reported normal percentages of circulating mDCs in aged humans. However, Della Bella et al. (2007) reported a decline in the percentage and numbers of mDCs in aged subjects. Similarly both normal and decreased numbers of pDCs have been reported in aged humans (Agrawal et al., 2007; Canaday et al., 2010; Jing et al., 2009; Perez-Cabezas et al., 2007; Shodell and Siegal, 2002). Several factors, including variability in donor population may account for some of the conflicting data. In our study, aged mDCs and pDCs were similar in numbers and phenotype to DCs from young (Agrawal et al., 2007). Further confirmation was obtained from the Affymetrix data which did not reveal any major difference in the gene expression profile of DC phenotypic markers (data not shown). Furthermore, in vitro exposure of mDCs to LPS resulted in comparable levels of activation between the aged and young mDCs as measured by upregulation of CD40, CD80, CD86 CD83 and HLA-DR. Lung et al. (2000) also reported similar findings. This would suggest that the differentiation and maturation of mDCs in vitro does not change during aging. 2.2. Pro- and anti-inflammatory cytokine production by mDCs in aging In aging, increased plasma levels of proinflammatory cytokines have been reported (Bruunsgaard et al., 2001; Fagiola et al., 1993; Rink and Kirchner, 1998); however, the cellular sources are not defined, though aged B cells have been demonstrated to produce an increased amount of pro-inflammatory cytokines following leptin stimulation (Gupta et al., 2013). When mDCs from young and aged humans were stimulated with LPS (via TLR4) and ss-RNA (via TLR7), aged DCs secrete significantly higher levels of IL-6 and TNF-α, whereas IL-10, IL-12p70 and IL-12-p40 secretion was comparable (Agrawal et al., 2007). However, Lung et al. (2000) observed no difference in proinflammatory cytokine secretion between young and aged. Agrawal et al. (2009) and Panda et al. (2010) have observed increased basal levels of pro-inflammatory cytokines in aged DCs. DCs play an important role in inflammation and clearing of infections. DCs present at the sites of pathogen entry ‘sample’ their environment by phagocytosis, initiating specific immune responses when they sense microbes. The efficient uptake of pathogens is thus essential for the generation of immunity against microbes. Since uptake of apoptotic bodies is associated with anti-inflammatory response, we examined the capacity of young and aged mDCs to uptake apoptotic cells, of lucifer yellow as an example of micropinocytosis, and uptake of FITC-conjugated dextran as an example of endocytosis (Agrawal et al., 2007). An impairment of uptake of all three was observed suggesting that there is global defect of uptake of antigens by aged mDCs rather than just an impairment of phagocytosis of apoptotic cells, which may also explain, at least in part, impaired priming of T cells by aged DCs, and late necrosis of apoptotic cells resulting in inflammation and exposure to self antigens resulting in autoimmunity in aging. The receptors involved in these function including C1qR, CD36, α4β5, and mannose receptors were normal (data not shown). Furthermore, we showed that aged mDCs produced proinflammatory cytokines instead of anti-inflammatory cytokines following uptake of apoptotic cells. The PI3Ks (phospholipid inositol 3 kinases) are a conserved family of signal transduction enzymes that are involved in regulating cellular activation, inflammatory responses, chemotaxis, and apoptosis (Fukao and Koyasu, 2003; Martin et al., 2003). PKB/Akt is a downstream target of PI3K and plays a key role in cellular processes such as glucose

metabolism, cell proliferation, apoptosis, transcription and cell migration. One of the major findings of our study is that the phosphorylation of AKT in response to LPS is reduced in mDCs from aged individuals (Agrawal et al., 2007). AKT is known to play a major role in cytoskeleton motility and survival in DCs. Defective functioning of this pathway is reported to result in decreased phagocytosis and migration of DCs. Recent evidence indicates that the PI3K/Akt signaling pathway may also function as an endogenous negative feedback or compensatory mechanism that serves to limit pro-inflammatory response to injurious stimuli. Reports indicate that there is cross talk between the TLR and PI3K/Akt signaling pathways. Fukao and Koyasu (2003) reported that PI3K may be an endogenous negative feedback regulator of TLRmediated inflammatory responses. Martin et al. (2003) have shown how the TLR and PI3K pathways serve to balance pro-inflammatory and anti-inflammatory responses. Our findings of reduced phosphorylation of AKT and concomitant increased phosphorylation of p38 MAPkinase in DCs from aging is in agreement with above observations regarding a role of PI3K in the regulation of inflammatory response. We also showed an impaired migration of LPS-stimulated aged DCs in response to MIP-3β and SDF, which is independent of chemotactic factor receptors, since chemokine receptor expression are comparable between young and aged. A role of PI3-K pathway in impaired mDC functions in aged was supported by the observation that the treatment of young mDCs from with PI3K inhibitor LY294002 inhibited LPS-induced phosphorylation AKT with concomitant increased p38 phosphorylation, which is associated with decreased uptake of antigen, decreased migration, and increased cytokine production (Agrawal et al., 2007). Therefore, an impaired function of PI3K signaling pathway in aging may be responsible for altered mDC functions resulting in enhanced secretion of pro-inflammatory cytokine secretion and simultaneous impairment of antigen uptake and migration of DCs. PI3Kinase/AKT is regulated by a variety of intracellular and extracellular signals and PTEN has emerged as one of its major negative regulators (Simpson and Parsons, 2001). PTEN expression was increased at both message and protein level, which may be responsible for impaired PI3K pathway in aged DCs. A defect in phagocytosis of apoptotic cells by the DCs in aged may result in late necrosis of apoptotic cells resulting in an induction of inflammatory response and exposure of self-antigens resulting in autoimmunity in aged humans. We also observed increased basal levels of activated NF-κB (p65) along with increased basal levels of TNF-α, which may explain chronic inflammatory state in aging (Agrawal et al., 2009). Increased basal levels of TNF-α in aged have also been reported by Panda et al. (2010). 3. Role of DCs in autoimmunity in aging In contrast to the progressive decline in immune functions with advancing age, there is an increased reactivity to self and endogenous antigens as evidenced by the presence and increased titers of a variety of autoantibodies (Manavalan et al., 1998; Rowley et al., 1968; Tomer and Shoenfeld, 1988; Weksler and Goodhardt, 2002), which suggest a loss of peripheral tolerance in aging. The information regarding mechanisms of impaired tolerance in human aging is limited. Apoptosis plays an important role in the effector functions and immune homeostasis. One of the critical steps in apoptosis is a rapid uptake of apoptotic cells and apoptotic bodies by neighboring phagocytic cells, resulting in intracellular degradation of self-antigens, and induction of antiinflammatory response and generation of Treg. We have shown that in aging, apoptosis is increased (Aggarwal and Gupta, 1998; Aggarwal et al., 1999; Gupta, 2000, 2005) whereas DCs are impaired in their capacity to uptake apoptotic cells (Agrawal et al., 2007). As a consequence apoptotic cells would undergo secondary necrosis with additional proteolytic degradation of specific autoantigens, which may release endogenous danger signals like nuclear antigens clustered in apoptotic blebs and bodies (e.g. chromatic, DNA, RNA, and histones),

Please cite this article as: Gupta, S., Role of dendritic cells in innate and adaptive immune response in human aging, Exp. Gerontol. (2014), http:// dx.doi.org/10.1016/j.exger.2013.12.009

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resulting in maturation of DCs, and T cell immunity to self antigens, and stimulating autoantibody responses. 3.1. Increased reactivity of aged DCs to self-DNA DCs are unique antigen-presenting cells because of their capacity to prime naïve T cells (Banchereau et al., 2000). DCs therefore function as initiators of T cell immunity. DCs can prime or tolarize T cells. Under physiological conditions, DCs play a role in unresponsiveness to selfantigens. DCs are essential for both central and peripheral tolerance. Impaired clearance of apoptotic cells has been implicated in autoimmune diseases like lupus (Hardin, 2003; Shoshan and Mevorach, 2004). Therefore, we compared priming capacity of young and aged DCs to self DNA. DNA was purified from young humans and delivered intracellularly to mDCs from young and aged subjects and examined for activation, cytokine production and T cell proliferation (Agrawal et al., 2009). DNA-primed mDCs from aged subjects upregulated costimulatory molecules, and secreted increase levels of IL-6 and IFN-α as compared to young mDCs. Similar increased in cytokine secretion was observed by aged mDCs in response to late apoptotic cells. Furthermore, young DNA-primed aged mDCs induced autologous T cell proliferation, whereas young DNA-primed young mDCs did not induce T cell proliferation, suggesting a role of DCs in increased reactivity to self-DNA and a loss of tolerance in aged humans. This increased reactivity to DNA is independent of TLR-9. Furthermore, expression of the cytosolic DNA sensor DAM1 was comparable between young and aged, suggesting steps downstream of cytosolic sensors may be involved in self-reactivity to DNA by aged DCs. Since there are several DNA censors, a possibility of involvement of one of the other DNA sensors cannot be excluded. One of the steps downstream of DNA censors is the interferon-responsive factor-3 (IRF-3). We observed an increased activation of IRF-3 transcription factor in mDCs from aged in response to intracellular self-DNA (Agrawal et al., 2009). Furthermore, mDCs from aged display higher basal levels of NF-κB activation, suggesting that DCs from aged are in an activated state. Panda et al. (2010) also observed increased basal levels of cytokines in aged DCs. In summary, mDCs from aged display increased reactivity to intracellular DNA as evidenced by increased T cell proliferation, and induction of secretion of proinflammatory cytokines (IFN-α, IL-6, TNF-α), the latter appears to be mediated via increased NF-κB activity. 3.2. Epigenetic modifications in aging DNA increase its immunogenicity Epigenetic regulation of gene expression occurs via chemical modification such as histone acetylation and methylation, without alteration in the nucleotide sequence in the genome (Feinberg, 2007). Human DNA undergoes age-associated genetic and epigenetic changes (Chen et al., 2009; Richardson, 2002). During aging, cells and tissues become hypomethylated while selected genes become progressively hypermethylated (Issa, 2003). There is a relationship between genomic instability, DNA damage, and DNA repair mechanisms in aging are impaired resulting in DNA lesions with single and double-stranded breaks (Lombard et al., 2005). Furthermore, oxidative damage to DNA has been implicated in aging and age-related degenerative disorders (Martien and Abbadie, 2007). Human DNA is generally inert and does not stimulate DCs. We show that DNA from aged mononuclear cells when introduced into young mDCs resulted in upregulation of co-stimulatory molecules CD80 and CD86, and increased secretion of IFN-α, as compared to young DNA, suggesting an increased immunogenicity of aged DNA (Agrawal et al., 2010). We showed that DNA from aged subjects is hypomethylated, and when aged DNA was hypermethylated comparable to methylation of young DNA, aged DCs could no longer induced increased secretion of IFN-α, demonstrating that immunogenicity of mammalian DNA correlates inversely with DNA methylation. Furthermore, we show that intracellular delivery of oxidative-damaged DNA did not result in the

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activation of mDCs, which suggest that DNA damage per se does not increase immunogenicity of aged DNA, and hypomethylation of DNA is responsible for its increased immunogenicity in aging. It remains to be determined which site-specific hypomethylation confer increased immunogenicity to self-DNA. In summary, DCs from aged humans demonstrate impaired signaling through PI3K pathways and increased reactivity to self antigen (DNA) resulting in increased inflammation, decreased migration and uptake of antigens, and increased reactivity to DNA (autoimmunity), which appears to be due to alterations in both aged DCs and aged DNA. 4. Increased susceptibility to viral infections in human aging Innate immunity is the first line of defense against invading pathogens. Secretion of interferons (IFNs) from virus-infected cells is a hallmark of host antiviral immunity. In addition, interferons affect the functions of innate and adaptive immunity (Fig. 1). IFN-I promotes the differentiation of naïve CD4 + T cells to TH1 cells, and survival of activated T cells, and enhances the cytotoxicity of CD8 + T cells and NK Cells (Farrar et al., 2000; Marrack et al., 1999; Rogge et al., 1998). In addition, IFN-I enhances antibody production, and induces isotype class switch in B cells (Braun et al., 2000; Jego et al., 2003; Le Bon et al., 2006). Furthermore, IFN-I enhances antigen cross presentation and maturation of DCs by upregulating co-stimulatory molecules and TLRs, and inducing secretion of pro-inflammatory cytokines (Beignon et al., 2003; Tough, 2004). IFN-III plays a major role in viral defense; however, provides much better protection at mucosal surfaces than IFN-I (Ank and Paludan, 2009), especially against influenza A virus, influenza B virus, and respiratory syncytial virus, which are more common in elderly subjects (Jewell et al., 2010; Mordstein et al., 2008, 2010). DCs are major producers of both IFN-I (IFN-α, IFN-β, IFN-κ, IFN-ω) and IFN-III [IFN-λ1 (IL-29), λ2 (IL-28a), λ3 (IL-28b)]. mDCs produce greater amount of IFN-III, whereas pDCs are major source of IFN-I (Banchereau et al., 2000; Fitzgerald-Bocarsly et al., 2008; Miriam and Manz, 2009). pDCs from aged are impaired in secreting IFN-I and IFN-III in response to influenza virus and CpG (Abb et al., 1984; Panda et al., 2010; Shodell and Siegal, 2002; Sridharan et al., 2010; Teig et al., 2002). However, the expression of TLR7 and TLR9 on aged pDCs is comparable to young (Sridharan et al., 2010). Furthermore, we demonstrated that the expression of downstream signaling molecules IRAK-1, Myd88, and IRF-7 in aging pDCs is comparable to young; however, CpG and influenza virus-induced IRF-7 phosphorylation in aged pDCs are impaired (Sridharan et al., 2010). pDCs from aged are impaired in priming CD8+ T cells as determined by proliferation, perforin and granzyme production, and IFN-γ production (Sridharan et al., 2010). pDCs are also impaired in priming of CD4 + T cells as determined by CD4 + T cell proliferation. We also examined a role of mDCs in responses to influenza virus (Prakash et al., 2012). The phenotype of aged and young mDCs was comparable following activation with heat-inactivated influenza virus. However, mDCs from aged were impaired in their ability to produce influenza virus-induced IFN-I and IFN-III. Panda et al. (2010) also demonstrated decreased IFN-I production in aged mDCs. We examine whether histone modifications (epigenetic changes) play a role in impaired interferon secretion by mDCs in aged humans (Prakash et al., 2012). Association of IFN-A2 and IFN-λ1 (IL-29) promoter to H3K4me3 and H3K9me3 is altered in aged DCs. This impaired association was specific to IFN-A2 and IFN-λ1 since no such impairment of association was observed between histones and TNF-α promoter, and no association of IFN-2A, and IL-29 (IFN-λ) non-promoter to H3K4me3 and H3K9me3 was observed. Additionally association of IFN-A2, IFN-λ, TNF-α promoter to H3K4me and HeK9me in aged mDCs is unstable. IFNs exert their antiviral activities through the induction of antiviral proteins (Zhou et al., 2013). The IFN-induced protein with tetratricopeptide repeats (IFITs) family is among the hundreds of IFN-

Please cite this article as: Gupta, S., Role of dendritic cells in innate and adaptive immune response in human aging, Exp. Gerontol. (2014), http:// dx.doi.org/10.1016/j.exger.2013.12.009

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Fig. 1. Role of interferons in innate and adaptive immunity. mDCs/pDCs upon activation with viruses, CpG, or immune complexes secrete both IFN-I and IFN-III. IFN-I activated CD8+ T cells and NK cells to increased cytotoxicity, and polarize naïve CD4+ T cells to IFN-γ producing TH1 cells. IFN-I also induce proliferation of B cells, isotype switch, and differentiation into antibody producing B cells and plasma cells. IFN-III plays predominant role in maintaining integrity of epithelial cells. IFN-I and IFN-III, in an autocrine and paracrine manner, further activate DCs to induce secretion of CXCR3 chemokines, proinflammatory cytokines (IL-6, TNF-α) and antimicrobial peptide.

stimulated genes. This family contains a cluster of duplicated loci. Most mammals have IFIT1, IFIT2, IFIT3 and IFIT5. IFIT family genes are predominantly induced by type I and type III interferons and are regulated by the pattern recognition and the JAK-STAT signaling pathway. IFIT family proteins are involved in many processes in response to viral infection. The IFIT family shows potent antiviral ability so it is conceivable that these proteins also influence the innate immune response. IFIT1 negatively regulates cellular antiviral response by disrupting the interaction of the MITA (mediator of IRF3 activation), MAVS (mitochondrial antiviral signaling protein) and TBK1 (TANK-binding kinase 1), which transfer signaling from RLRs recognized pathogens. Over-expression of IFIT1 could inhibit virus-triggered activation of IFN-β, NF-κB and IRF3. In addition, IFIT2 is also a MITA-associated protein, and induces apoptosis via the mitochondrial pathway that is induced by the innate immune response. IFIT3 could block apoptosis by binding IFIT2. Our gene array data show significantly decreased gene expression of IFIT1 and IFIT3 in aged mDCs as compared to young mDCs (manuscript in preparation). Both IFN-α and IFN-β have been shown to mediate their effects though a common IFNAR1 and IFNAR2 (de Weerd et al., 2007; Fensterl and Sen, 2008). However, recently it has been reported that IFN-β may not use IFNR2 and uses a different partner with IFNAR1 (de Weerd et al., 2013). The expression of IFNAR1/2 and response to INF-β remains to be studied. At the gene level, IFNR2 expression is decreased in mDCs in aged humans (manuscript in preparation). 5. Role of DCs in hyperimmunoglobulinemia in aging A polyclonal hyperimmunoglobulinemia is a commonly observed in human aging (Manavalan et al., 1998; Tomer and Shoenfeld, 1988). T-follicular helper (Tfh) cells are a new subset of effector CD4+ T cells that are specialized in helping B cells in the germinal center reaction (Ma et al., 2009; Schmitt et al., 2009). DCs induce polarization of naïve CD4+ T cells to IL-21 producing Tfh cells. IL-21 stimulates B cell proliferation, and differentiation into Ig producing B cells and long lived plasma cells (Ozaki et al., 2002). Though Tfh cells are comparable in aged and young subjects, the aged CD4+ T cells secrete increased levels

of IL-21. However, an increased IL-21 secretion from aged CD4+ T cells is not due to age-associated alterations in DC functions. Aged naïve CD4+ T cells are more sensitive to differentiation by IL-12 as compared to young naïve CD4+ T cells. The expression of IL-12R on naïve CD4+ T cells is comparable between young and aged; however, STAT-4 phosphorylation is sustained in aged CD4 + T cells as compared to naïve CD4 + T cells. Furthermore, increased IL-21 secretion in aged T cells correlates with CMV seropositivity (Agrawal et al., 2012). In summary, in aged humans, pDC and mDCs phenotypically and morphologically appear to be normal and in vitro differentiation of mDCs from monocytes also appears to be normal. However, mDCs are impaired in endocytosis, micropinocytosis, phagocytosis, and migration, which appear to be, in part, due to impaired PI3K signaling pathway. Impaired migration of DCs may contribute to T cell priming and T cell deficiency in aging. A defect in phagocytosis of apoptotic cells by aged mDCs resulting in late necrosis may contribute to inflammation and exposure of self-antigens contributing to autoimmunity in aging. In addition, mDCs display increased basal levels of NF-κB and TNF-α, which may also contribute to chronic inflammation associated with aging. The mDCs are impaired in their capacity to prime naïve CD4+ and CD8 + T cells. In contrast, aged mDC induce T cell proliferation to self-DNA, which appears to be due to both altered DC functions and epigenetic changes (hypomethylation) of aged DNA. pDCs are impaired in their capacity to produce Type I and type III IFNs in response to TLR7 (heat-killed influenza) and TLR9 (CpG) stimulation, which appears to be due to decreased phosphorylation of IRF-7. pDCs also impaired in priming CD4 + and CD8 + T cell responses as evidenced by decreased proliferation of both CD4+ and CD8+ T cells, and production of IFN-γ, granzyme and perforin by CD8 + T cells. Aged mDCs are also impaired to produce IFN-I and IFN-III, which is associated with abnormal histone modification. An impaired IFN-I and IFN-III production may be responsible for increased susceptibility to viral infections in aged humans. It appears that in aged humans DCs, response to normal stimuli is impaired resulting in immunodeficiency, whereas they respond to self-antigen resulting in inflammation and autoimmunity.

Please cite this article as: Gupta, S., Role of dendritic cells in innate and adaptive immune response in human aging, Exp. Gerontol. (2014), http:// dx.doi.org/10.1016/j.exger.2013.12.009

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Conflict of interest The authors have no conflicts of interests.

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Please cite this article as: Gupta, S., Role of dendritic cells in innate and adaptive immune response in human aging, Exp. Gerontol. (2014), http:// dx.doi.org/10.1016/j.exger.2013.12.009