Phospholipid signals of microbial infection for the human immune system Mitchell Kronenberga,b,1 and Meng Zhaoa,b
The immune system must defend the body from pathogens while avoiding self-reactivity leading to autoimmune disease. This discrimination depends upon distinguishing molecular structures that are autologous, or self, from those structures that are nonself. Although self–nonself discrimination is a cardinal feature of immune recognition, self-reactivity is evident in various populations of T lymphocytes, although the degree of self-reactivity varies and in some cases can be weak. Interestingly, some self-reactive T cells also display cross-reactivity for microbial antigens (Table 1). In PNAS, Van Rhijn et al. define the cross-reacting bacterial and self-antigens of a group of T lymphocytes that respond to antigens bound to or presented by CD1b (1). Their findings suggest one mechanism whereby dangerous, CD1mediated self-reactivity by T cells might be controlled, and the authors provide a hypothesis for why cross-reactive recognition of the antigens they define might be useful. The T-cell antigen receptor (TCR) expressed by the majority of human T lymphocytes is a heterodimer consisting of α and β chains. CD4+ αβ T cells recognize peptide fragments presented by class II antigenpresenting molecules encoded in the MHC, whereas CD8+ αβ T cells respond to peptides presented by MHC class I proteins. The genes encoding MHC class I and class II proteins are highly polymorphic. Homologs of these genes, however, encode antigen-presenting molecules that are not polymorphic. Prominent among these nonpolymorphic antigen-presenting molecules is the CD1 family, which has highly hydrophobic antigen-binding grooves that present lipids (2). In humans there are four CD1 proteins: the group I proteins include CD1a, CD1b, and CD1c. CD1d is the single member of the more distantly related group 2 (2). Each of these proteins traffics differentially through endosomes and lysosomes to acquire antigens (3). For example, CD1a recycles predominantly through early endosomes. In contrast, CD1b traffics deep into lysosomes, where it can acquire antigens (3). Until recently, characterization of the antigens presented by the group 1 CD1 molecules depended on long-term T-cell clones, and the antigens were almost entirely derived from Mycobacteria tuberculosis
and related species (4). This was not surprising, because mycobacteria have a complex mixture of cell wall lipids with diverse structures. Perhaps more surprising was the finding that a number of the CD1reactive long-term lines exhibited self-reactivity (5), although until recently the antigens were not identified. A population of CD1d-reactive T lymphocytes, known as invariant natural killer T cells, reacts with microbial glycosphingolipid (GSL) and glycosylated diacylglycerol (DAG) antigens (6), and is also selfreactive to CD1d, although the nature of the self-antigens remains controversial (7, 8). Additionally, in humans, T cells expressing a TCR composed of γ and δ chains are a relatively low-frequency population compared with αβ T cells, but some of these γδ T cells are known to be selfreactive as well, either for isopentenyl pyrophosphate generated from the endogenous mevalonate pathway (9, 10), or from various glycolipid antigens, including sulfatide presented by CD1d and phospholipids presented by CD1c and other CD1 molecules (11, 12). A breakthrough in the study of T lymphocytes reactive to group I CD1 molecules came with the development of tetramers that can be used in flow cytometry to detect low-frequency cells based on their TCR specificity (13). The underlying principle is that TCR interactions have a relatively low affinity, in the micromolar range, but this can be overcome by providing tetramers, for example in this case tetramers of a lipid antigen bound to the relevant group 1 CD1 molecule. Tetramers are produced by constructs that encode a soluble form of the antigen-presenting molecule with a short sequence that can be enzymatically biotinylated by a bacterial enzyme. Tetramers are formed by reacting the biotinylated protein with streptavidin conjugated to a fluorophore convenient for use in flow cytometers. To search for antigens presented by CD1b from microbes other than mycobacteria, Van Rhijn et al. (1) used dextramers, a variant of the tetramer method formed by conjugating CD1b-lipid complexes to dextran backbones that have a higher valency than tetramers (14). They loaded the CD1b molecules with lipid extracts from bacterial pathogens, such as Staphylococcus aureus, Brucella melitensis, and Salmonella
a
Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; and bDivision of Biology, University of California, San Diego, La Jolla, CA 92037 Author contributions: M.K. and M.Z. wrote the paper. The authors declare no conflict of interest. See companion article on page 380. 1 To whom correspondence should be addressed. Email: [email protected].
www.pnas.org/cgi/doi/10.1073/pnas.1522318113
PNAS | January 12, 2016 | vol. 113 | no. 2 | 251–253
COMMENTARY
COMMENTARY
Table 1. Human self-reactive T cells Ag presenting molecule Butyrophilin? CD1a CD1b CD1c CD1d
TCR Vγ9 (TRGV2S1)/ Vδ2 (TRDV102S1) Diverse αβ TCRs Diverse αβ TCRs Diverse αβ TCRs? γδ TCRs with Vδ1 (TRDV1) Vα24 (TRAV10)/ Jα18 (TRAJ18) Diverse αβ γδ TCRs with Vδ1 (TRDV1)
Self Ag specificity
Foreign Ag specificity
Refs.
Isopentenylpyrophosphate (IPP) Squalene, wax esters, and triacylglycerides PGs Methyl-lysophosphatidic acids (mLPAs), phospholipids GSLs, phospholipids
(E)-4-hydroxy-3-methyl-but-2enylpyrophosphate (HMBPP)
(9, 10, 18)
GSLs, phospholipids
(15) PGs
(1) (11, 19)
Several bacterial and fungal GSLs and glycosylated DAGs Phospholipids
(6–8) (11, 12, 20)
Human autoreactive T-cell populations with defined specificity. Where a cross-reactivity of the self-reactive T cells for a microbial antigen is known, this is indicated. DAG, diacylglycerol; GSL, glycosphingolipid; PG, phosphatidylglycerol.
typhimurium. Van Rhijn et al. (1) were able to detect cells reactive with the antigen-loaded CD1b dextramers from the peripheral blood of healthy donors at a frequency of ∼1 in 105. The T cells from two donors were sorted and expanded to generate cell lines for further analysis, and two unexpected results emerged. The first result is that CD1b-dependent reactivity could be detected at all, because tetramers usually are useful only when the antigen-presenting molecule is loaded with a homogenous antigen, required to provide the increase in valency. The advantage in these experiments, however, likely was the relatively simple lipidome of the microbes compared with mycobacteria, and the increased valency the dextramers provided. Chemical analysis by mass spectrometry indicated that the antigens were phospholipids, namely phosphatidylglycerol (PG). The second unexpected finding was that the cell lines expanded by bacterial antigens reacted to mammalian cells that expressed CD1b, in the absence of any microbial antigen. To explore this self-reactivity further, CD1b dextramers were loaded with synthetic or purified mammalian versions of phospholipids, including PG but also phosphatidic acid (PA), phosphatidylcholine (PC), phosphatidylinositol (PI), and others. Although there were differences in the reactivity pattern of the two cell lines for different phospholipids, they reacted strongly to both PG and PA. The cell lines likely contained many clones, but the specificity of TCRs from single cells for phospholipids from multiple bacterial sources and mammalian cells was demonstrated by cloning and expressing two αβ TCR pairs, which were assayed for tetramer binding and T-cell activation. How is the autoreactivity for mammalian PGs controlled to prevent tissue damage? One idea is that a complex mixture of cellular lipids presented by CD1b regulates autoreactivity, with some self-glycolipids being inhibitory. This model, in which the balance of stimulating and inhibiting lipids regulates autoimmune responses, appears to be the case for skin homing CD1a autoreactive T cells specific for hydrophobic skin oils (15). These antigens fill the CD1a hydrophobic groove or pocket, a requirement for stable CD1 expression, but they do not have a hydrophilic head group emerging from the top of the CD1a protein for TCR recognition (15). Therefore, in these cells the main TCR contacts are with CD1a itself, and some larger hydrophilic head groups actually inhibited the response. Hydrophobic skin oils are not normally in contact with the epidermal and dermal layers where the CD1a self-reactive T cells are located, and therefore these T cells might only encounter antigens when the skin barrier is damaged by injury.
252 | www.pnas.org/cgi/doi/10.1073/pnas.1522318113
The mixture of inhibitory and stimulatory self-lipids likely does regulate the degree of CD1b-mediated stimulation, because when CD1b multimers were loaded with GSLs having larger carbohydrate head groups, the background staining from CD1b protein produced in mammalian cells was reduced. The fine specificity of the CD1b self-reactive T cells for different phospholipids based on their hydrophilic head groups, for example comparing the responses to PI and PC, suggests however that reactivity mediated exclusively by the roof of the antigenpresenting molecule does not apply to CD1b autoreactive T cells. Another hypothesis is that differences in the buried lipid components of the antigens are important, either because they determine the ability of the antigen to bind to CD1b or the precise orientation of the exposed phosphate group for TCR binding. Consistent with this possibility, the fatty acids of bacterial PGs often have methyl branches and cyclopropyl groups that are not present in their mammalian counterparts, which could provide additional antigenic potency. The dextramer staining results do not provide support for this hypothesis, however, because the binding of dextramers loaded with either bacterial or a synthetic mammalian PG was essentially identical. Van Rhijn et al. (1) therefore propose a third model based on the fact that PGs are highly expressed by many bacteria, much more than in mammalian cells (16). CD1b-mediated recognition of PGs therefore might be useful because it provides a signal for infection with a wide variety of bacteria. PGs are synthesized in mitochondria in mammalian cells (17), and the authors speculate that self-reactivity might be controlled not only by their limited amount, but also by limited access to antigen, with autoreactivity induced when mitochondria are stressed. This appealing model requires further confirmation, but it is has two important implications. First, T-cell recognition of PGs presented by CD1b has a dual function: recognition of microbes and recognition of stressed cells, a theme that is observed in some other T-cell populations exhibiting autoreactivity (Table 1). Second, as for the CD1a autoreactive T cells, limiting the access of the antigen-presenting molecule to the self-antigen controls self-reactivity. For CD1a autoreactivity, it is the physical barrier of dead skin cells controlling access, whereas for CD1b autoreactivity, the low antigen concentration and sequestration in mitochondria may be most important. The dichotomy of self–nonself discrimination therefore needs revision, as these and other cases listed (Table 1) provide significant examples in the immune system of useful autoreactivity carried out by diverse populations of T lymphocytes. These studies emphasize the fact that discrimination
Kronenberg and Zhao
of self–nonself by the immune system is not always a black-and-white decision, and that various mechanisms regulate T-cell responses to
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
ensure that under certain circumstances self-recognition beneficial to the organism can occur.
Van Rhijn I, et al. (2015) Human autoreactive T cells recognize CD1b and phospholipids. Proc Natl Acad Sci USA 113:380–385. Adams EJ (2014) Lipid presentation by human CD1 molecules and the diverse T cell populations that respond to them. Curr Opin Immunol 26:1–6. Moody DB, Porcelli SA (2003) Intracellular pathways of CD1 antigen presentation. Nat Rev Immunol 3(1):11–22. Van Rhijn I, Ly D, Moody DB (2013) CD1a, CD1b, and CD1c in immunity against mycobacteria. Adv Exp Med Biol 783:181–197. Porcelli S, et al. (1989) Recognition of cluster of differentiation 1 antigens by human CD4-CD8-cytolytic T lymphocytes. Nature 341(6241):447–450. Kinjo Y, Kitano N, Kronenberg M (2013) The role of invariant natural killer T cells in microbial immunity. J Infect Chemother 19(4):560–570. Gapin L, Godfrey DI, Rossjohn J (2013) Natural killer T cell obsession with self-antigens. Curr Opin Immunol 25(2):168–173. Kim J, Kim JH, Winau F (2014) Thinking inside the box: Endogenous α-anomeric lipid antigens. Immunity 41(4):505–506. Bürk MR, Mori L, De Libero G (1995) Human V gamma 9-V delta 2 cells are stimulated in a cross-reactive fashion by a variety of phosphorylated metabolites. Eur J Immunol 25(7):2052–2058. Tanaka Y, et al. (1995) Natural and synthetic non-peptide antigens recognized by human gamma delta T cells. Nature 375(6527):155–158. Russano AM, et al. (2007) CD1-restricted recognition of exogenous and self-lipid antigens by duodenal gammadelta+ T lymphocytes. J Immunol 178(6): 3620–3626. Bai L, et al. (2012) The majority of CD1d-sulfatide-specific T cells in human blood use a semiinvariant Vδ1 TCR. Eur J Immunol 42(9):2505–2510. Kasmar AG, et al. (2011) CD1b tetramers bind αβ T cell receptors to identify a mycobacterial glycolipid-reactive T cell repertoire in humans. J Exp Med 208(9): 1741–1747. Batard P, et al. (2006) Dextramers: new generation of fluorescent MHC class I/peptide multimers for visualization of antigen-specific CD8+ T cells. J Immunol Methods 310(1-2):136–148. de Jong A, et al. (2014) CD1a-autoreactive T cells recognize natural skin oils that function as headless antigens. Nat Immunol 15(2):177–185. Ray TK, Skipski VP, Barclay M, Essner E, Archibald FM (1969) Lipid composition of rat liver plasma membranes. J Biol Chem 244(20):5528–5536. Horvath SE, Daum G (2013) Lipids of mitochondria. Prog Lipid Res 52(4):590–614. Vavassori S, et al. (2013) Butyrophilin 3A1 binds phosphorylated antigens and stimulates human gamma delta T cells. Nat Immunol 14(9):908–916. Lepore M, et al. (2014) A novel self-lipid antigen targets human T cells against CD1c(+) leukemias. J Exp Med 211(7):1363–1377. Tatituri RV, et al. (2013) Recognition of microbial and mammalian phospholipid antigens by NKT cells with diverse TCRs. Proc Natl Acad Sci USA 110(5): 1827–1832.
Kronenberg and Zhao
PNAS | January 12, 2016 | vol. 113 | no. 2 | 253
The immune system must defend the body from pathogens while avoiding self-reactivity leading to autoimmune disease. This discrimination depends upon distinguishing molecular structures that are autologous, or self, from those structures that are nonself. Although self–nonself discrimination is a cardinal feature of immune recognition, self-reactivity is evident in various populations of T lymphocytes, although the degree of self-reactivity varies and in some cases can be weak. Interestingly, some self-reactive T cells also display cross-reactivity for microbial antigens (Table 1). In PNAS, Van Rhijn et al. define the cross-reacting bacterial and self-antigens of a group of T lymphocytes that respond to antigens bound to or presented by CD1b (1). Their findings suggest one mechanism whereby dangerous, CD1mediated self-reactivity by T cells might be controlled, and the authors provide a hypothesis for why cross-reactive recognition of the antigens they define might be useful. The T-cell antigen receptor (TCR) expressed by the majority of human T lymphocytes is a heterodimer consisting of α and β chains. CD4+ αβ T cells recognize peptide fragments presented by class II antigenpresenting molecules encoded in the MHC, whereas CD8+ αβ T cells respond to peptides presented by MHC class I proteins. The genes encoding MHC class I and class II proteins are highly polymorphic. Homologs of these genes, however, encode antigen-presenting molecules that are not polymorphic. Prominent among these nonpolymorphic antigen-presenting molecules is the CD1 family, which has highly hydrophobic antigen-binding grooves that present lipids (2). In humans there are four CD1 proteins: the group I proteins include CD1a, CD1b, and CD1c. CD1d is the single member of the more distantly related group 2 (2). Each of these proteins traffics differentially through endosomes and lysosomes to acquire antigens (3). For example, CD1a recycles predominantly through early endosomes. In contrast, CD1b traffics deep into lysosomes, where it can acquire antigens (3). Until recently, characterization of the antigens presented by the group 1 CD1 molecules depended on long-term T-cell clones, and the antigens were almost entirely derived from Mycobacteria tuberculosis
and related species (4). This was not surprising, because mycobacteria have a complex mixture of cell wall lipids with diverse structures. Perhaps more surprising was the finding that a number of the CD1reactive long-term lines exhibited self-reactivity (5), although until recently the antigens were not identified. A population of CD1d-reactive T lymphocytes, known as invariant natural killer T cells, reacts with microbial glycosphingolipid (GSL) and glycosylated diacylglycerol (DAG) antigens (6), and is also selfreactive to CD1d, although the nature of the self-antigens remains controversial (7, 8). Additionally, in humans, T cells expressing a TCR composed of γ and δ chains are a relatively low-frequency population compared with αβ T cells, but some of these γδ T cells are known to be selfreactive as well, either for isopentenyl pyrophosphate generated from the endogenous mevalonate pathway (9, 10), or from various glycolipid antigens, including sulfatide presented by CD1d and phospholipids presented by CD1c and other CD1 molecules (11, 12). A breakthrough in the study of T lymphocytes reactive to group I CD1 molecules came with the development of tetramers that can be used in flow cytometry to detect low-frequency cells based on their TCR specificity (13). The underlying principle is that TCR interactions have a relatively low affinity, in the micromolar range, but this can be overcome by providing tetramers, for example in this case tetramers of a lipid antigen bound to the relevant group 1 CD1 molecule. Tetramers are produced by constructs that encode a soluble form of the antigen-presenting molecule with a short sequence that can be enzymatically biotinylated by a bacterial enzyme. Tetramers are formed by reacting the biotinylated protein with streptavidin conjugated to a fluorophore convenient for use in flow cytometers. To search for antigens presented by CD1b from microbes other than mycobacteria, Van Rhijn et al. (1) used dextramers, a variant of the tetramer method formed by conjugating CD1b-lipid complexes to dextran backbones that have a higher valency than tetramers (14). They loaded the CD1b molecules with lipid extracts from bacterial pathogens, such as Staphylococcus aureus, Brucella melitensis, and Salmonella
a
Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; and bDivision of Biology, University of California, San Diego, La Jolla, CA 92037 Author contributions: M.K. and M.Z. wrote the paper. The authors declare no conflict of interest. See companion article on page 380. 1 To whom correspondence should be addressed. Email: [email protected].
www.pnas.org/cgi/doi/10.1073/pnas.1522318113
PNAS | January 12, 2016 | vol. 113 | no. 2 | 251–253
COMMENTARY
COMMENTARY
Table 1. Human self-reactive T cells Ag presenting molecule Butyrophilin? CD1a CD1b CD1c CD1d
TCR Vγ9 (TRGV2S1)/ Vδ2 (TRDV102S1) Diverse αβ TCRs Diverse αβ TCRs Diverse αβ TCRs? γδ TCRs with Vδ1 (TRDV1) Vα24 (TRAV10)/ Jα18 (TRAJ18) Diverse αβ γδ TCRs with Vδ1 (TRDV1)
Self Ag specificity
Foreign Ag specificity
Refs.
Isopentenylpyrophosphate (IPP) Squalene, wax esters, and triacylglycerides PGs Methyl-lysophosphatidic acids (mLPAs), phospholipids GSLs, phospholipids
(E)-4-hydroxy-3-methyl-but-2enylpyrophosphate (HMBPP)
(9, 10, 18)
GSLs, phospholipids
(15) PGs
(1) (11, 19)
Several bacterial and fungal GSLs and glycosylated DAGs Phospholipids
(6–8) (11, 12, 20)
Human autoreactive T-cell populations with defined specificity. Where a cross-reactivity of the self-reactive T cells for a microbial antigen is known, this is indicated. DAG, diacylglycerol; GSL, glycosphingolipid; PG, phosphatidylglycerol.
typhimurium. Van Rhijn et al. (1) were able to detect cells reactive with the antigen-loaded CD1b dextramers from the peripheral blood of healthy donors at a frequency of ∼1 in 105. The T cells from two donors were sorted and expanded to generate cell lines for further analysis, and two unexpected results emerged. The first result is that CD1b-dependent reactivity could be detected at all, because tetramers usually are useful only when the antigen-presenting molecule is loaded with a homogenous antigen, required to provide the increase in valency. The advantage in these experiments, however, likely was the relatively simple lipidome of the microbes compared with mycobacteria, and the increased valency the dextramers provided. Chemical analysis by mass spectrometry indicated that the antigens were phospholipids, namely phosphatidylglycerol (PG). The second unexpected finding was that the cell lines expanded by bacterial antigens reacted to mammalian cells that expressed CD1b, in the absence of any microbial antigen. To explore this self-reactivity further, CD1b dextramers were loaded with synthetic or purified mammalian versions of phospholipids, including PG but also phosphatidic acid (PA), phosphatidylcholine (PC), phosphatidylinositol (PI), and others. Although there were differences in the reactivity pattern of the two cell lines for different phospholipids, they reacted strongly to both PG and PA. The cell lines likely contained many clones, but the specificity of TCRs from single cells for phospholipids from multiple bacterial sources and mammalian cells was demonstrated by cloning and expressing two αβ TCR pairs, which were assayed for tetramer binding and T-cell activation. How is the autoreactivity for mammalian PGs controlled to prevent tissue damage? One idea is that a complex mixture of cellular lipids presented by CD1b regulates autoreactivity, with some self-glycolipids being inhibitory. This model, in which the balance of stimulating and inhibiting lipids regulates autoimmune responses, appears to be the case for skin homing CD1a autoreactive T cells specific for hydrophobic skin oils (15). These antigens fill the CD1a hydrophobic groove or pocket, a requirement for stable CD1 expression, but they do not have a hydrophilic head group emerging from the top of the CD1a protein for TCR recognition (15). Therefore, in these cells the main TCR contacts are with CD1a itself, and some larger hydrophilic head groups actually inhibited the response. Hydrophobic skin oils are not normally in contact with the epidermal and dermal layers where the CD1a self-reactive T cells are located, and therefore these T cells might only encounter antigens when the skin barrier is damaged by injury.
252 | www.pnas.org/cgi/doi/10.1073/pnas.1522318113
The mixture of inhibitory and stimulatory self-lipids likely does regulate the degree of CD1b-mediated stimulation, because when CD1b multimers were loaded with GSLs having larger carbohydrate head groups, the background staining from CD1b protein produced in mammalian cells was reduced. The fine specificity of the CD1b self-reactive T cells for different phospholipids based on their hydrophilic head groups, for example comparing the responses to PI and PC, suggests however that reactivity mediated exclusively by the roof of the antigenpresenting molecule does not apply to CD1b autoreactive T cells. Another hypothesis is that differences in the buried lipid components of the antigens are important, either because they determine the ability of the antigen to bind to CD1b or the precise orientation of the exposed phosphate group for TCR binding. Consistent with this possibility, the fatty acids of bacterial PGs often have methyl branches and cyclopropyl groups that are not present in their mammalian counterparts, which could provide additional antigenic potency. The dextramer staining results do not provide support for this hypothesis, however, because the binding of dextramers loaded with either bacterial or a synthetic mammalian PG was essentially identical. Van Rhijn et al. (1) therefore propose a third model based on the fact that PGs are highly expressed by many bacteria, much more than in mammalian cells (16). CD1b-mediated recognition of PGs therefore might be useful because it provides a signal for infection with a wide variety of bacteria. PGs are synthesized in mitochondria in mammalian cells (17), and the authors speculate that self-reactivity might be controlled not only by their limited amount, but also by limited access to antigen, with autoreactivity induced when mitochondria are stressed. This appealing model requires further confirmation, but it is has two important implications. First, T-cell recognition of PGs presented by CD1b has a dual function: recognition of microbes and recognition of stressed cells, a theme that is observed in some other T-cell populations exhibiting autoreactivity (Table 1). Second, as for the CD1a autoreactive T cells, limiting the access of the antigen-presenting molecule to the self-antigen controls self-reactivity. For CD1a autoreactivity, it is the physical barrier of dead skin cells controlling access, whereas for CD1b autoreactivity, the low antigen concentration and sequestration in mitochondria may be most important. The dichotomy of self–nonself discrimination therefore needs revision, as these and other cases listed (Table 1) provide significant examples in the immune system of useful autoreactivity carried out by diverse populations of T lymphocytes. These studies emphasize the fact that discrimination
Kronenberg and Zhao
of self–nonself by the immune system is not always a black-and-white decision, and that various mechanisms regulate T-cell responses to
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
ensure that under certain circumstances self-recognition beneficial to the organism can occur.
Van Rhijn I, et al. (2015) Human autoreactive T cells recognize CD1b and phospholipids. Proc Natl Acad Sci USA 113:380–385. Adams EJ (2014) Lipid presentation by human CD1 molecules and the diverse T cell populations that respond to them. Curr Opin Immunol 26:1–6. Moody DB, Porcelli SA (2003) Intracellular pathways of CD1 antigen presentation. Nat Rev Immunol 3(1):11–22. Van Rhijn I, Ly D, Moody DB (2013) CD1a, CD1b, and CD1c in immunity against mycobacteria. Adv Exp Med Biol 783:181–197. Porcelli S, et al. (1989) Recognition of cluster of differentiation 1 antigens by human CD4-CD8-cytolytic T lymphocytes. Nature 341(6241):447–450. Kinjo Y, Kitano N, Kronenberg M (2013) The role of invariant natural killer T cells in microbial immunity. J Infect Chemother 19(4):560–570. Gapin L, Godfrey DI, Rossjohn J (2013) Natural killer T cell obsession with self-antigens. Curr Opin Immunol 25(2):168–173. Kim J, Kim JH, Winau F (2014) Thinking inside the box: Endogenous α-anomeric lipid antigens. Immunity 41(4):505–506. Bürk MR, Mori L, De Libero G (1995) Human V gamma 9-V delta 2 cells are stimulated in a cross-reactive fashion by a variety of phosphorylated metabolites. Eur J Immunol 25(7):2052–2058. Tanaka Y, et al. (1995) Natural and synthetic non-peptide antigens recognized by human gamma delta T cells. Nature 375(6527):155–158. Russano AM, et al. (2007) CD1-restricted recognition of exogenous and self-lipid antigens by duodenal gammadelta+ T lymphocytes. J Immunol 178(6): 3620–3626. Bai L, et al. (2012) The majority of CD1d-sulfatide-specific T cells in human blood use a semiinvariant Vδ1 TCR. Eur J Immunol 42(9):2505–2510. Kasmar AG, et al. (2011) CD1b tetramers bind αβ T cell receptors to identify a mycobacterial glycolipid-reactive T cell repertoire in humans. J Exp Med 208(9): 1741–1747. Batard P, et al. (2006) Dextramers: new generation of fluorescent MHC class I/peptide multimers for visualization of antigen-specific CD8+ T cells. J Immunol Methods 310(1-2):136–148. de Jong A, et al. (2014) CD1a-autoreactive T cells recognize natural skin oils that function as headless antigens. Nat Immunol 15(2):177–185. Ray TK, Skipski VP, Barclay M, Essner E, Archibald FM (1969) Lipid composition of rat liver plasma membranes. J Biol Chem 244(20):5528–5536. Horvath SE, Daum G (2013) Lipids of mitochondria. Prog Lipid Res 52(4):590–614. Vavassori S, et al. (2013) Butyrophilin 3A1 binds phosphorylated antigens and stimulates human gamma delta T cells. Nat Immunol 14(9):908–916. Lepore M, et al. (2014) A novel self-lipid antigen targets human T cells against CD1c(+) leukemias. J Exp Med 211(7):1363–1377. Tatituri RV, et al. (2013) Recognition of microbial and mammalian phospholipid antigens by NKT cells with diverse TCRs. Proc Natl Acad Sci USA 110(5): 1827–1832.
Kronenberg and Zhao
PNAS | January 12, 2016 | vol. 113 | no. 2 | 253
