Recognition of self and altered self by T cells in autoimmunity and allergy

Abstract

T cell recognition of foreign peptide antigen and tolerance to self peptides is key to the proper function of the immune system. Usually, in the thymus T cells that recognize self MHC+ self peptides are deleted and those with the potential to recognize self MHC+ foreign peptides are selected to mature. However there are exceptions to these rules. Autoimmunity and allergy are two of the most common immune diseases that can be related to recognition of self. Many genes work together to lead to autoimmunity. Of those, particular MHC alleles are the most strongly associated, reflecting the key importance of MHC presentation of self peptides in autoimmunity. T cells specific for combinations of self MHC and self peptides may escape thymus deletion, and thus be able to drive autoimmunity, for several reasons: the relevant self peptide may be presented at low abundance in the thymus but at high level in particular peripheral tissues; the relevant self peptide may bind to MHC in an unusual register, not present in the thymus but apparent elsewhere; finally the relevant self peptide may be post translationally modified in a tissue specific fashion. In some types of allergy, the peptide+ MHC combination may also be fully derived from self. However the combination in question may be modified by the presence of other ligands, such as small drug molecules or metal ions. Thus these types of allergies may act like the post translationally modified peptides involved some types of autoimmunity.

Keywords

altered self / neoantigen / antigen presenting / T cell recognition / autoimmunity / allergy / diabetes / dermatitis / drug hypersensitivity

References

[1] Ada, G.L., and Rose, N.R. (1988). The initiation and early development of autoimmune diseases. Clin Immunol Immunopathol 47, 3-9 .10.1016/0090-1229(88)90139-0
[2] Adams, J.J., Narayanan, S., Liu, B., Birnbaum, M.E., Kruse, A.C., Bowerman, N.A., Chen, W., Levin, A.M., Connolly, J.M., Zhu, C., . (2011). T cell receptor signaling is limited by docking geometry to peptide-major histocompatibility complex. Immunity 35, 681-693 .10.1016/j.immuni.2011.09.013
[3] Alarcon, B., Mestre, D., and Martinez-Martin, N. (2011). The immunological synapse: a cause or consequence of T-cell receptor triggering? Immunology 133, 420-425 .10.1111/j.1365-2567.2011.03458.x
[4] Allanore, Y., Saad, M., Dieude, P., Avouac, J., Distler, J.H., Amouyel, P., Matucci-Cerinic, M., Riemekasten, G., Airo, P., Melchers, I., . (2011). Genome-wide scan identifies TNIP1, PSORS1C1, and RHOB as novel risk loci for systemic sclerosis. PLoS Genet 7, e1002091.10.1371/journal.pgen.1002091
[5] Anderson, M.S., Venanzi, E.S., Klein, L., Chen, Z., Berzins, S.P., Turley, S.J., von Boehmer, H., Bronson, R., Dierich, A., Benoist, C., . (2002). Projection of an immunological self shadow within the thymus by the aire protein. Science 298, 1395-1401 .10.1126/science.1075958
[6] Banchereau, J., and Steinman, R.M. (1998). Dendritic cells and the control of immunity. Nature 392, 245-252 .10.1038/32588
[7] Bevan, M.J., and Hunig, T. (1981). T cells respond preferentially to antigens that are similar to self H-2. Proc Natl Acad Sci U S A 78, 1843-1847 .10.1073/pnas.78.3.1843
[8] Bluestone, J.A. (1995). New perspectives of CD28-B7-mediated T cell costimulation. Immunity 2, 555-559 .10.1016/1074-7613(95)90000-4
[9] Bluthmann, H., Kisielow, P., Uematsu, Y., Malissen, M., Krimpenfort, P., Berns, A., von Boehmer, H., and Steinmetz, M. (1988). T-cell-specific deletion of T-cell receptor transgenes allows functional rearrangement of endogenous alpha-and beta-genes. Nature 334, 156-159 .10.1038/334156a0
[10] Bogdanos, D.P., Smyk, D.S., Rigopoulou, E.I., Mytilinaiou, M.G., Heneghan, M.A., Selmi, C., and Gershwin, M.E. (2011). Twin studies in autoimmune disease: genetics, gender and environment. J Autoimmun 38, J 156-169 .10.1016/j.jaut.2011.11.003
[11] Brand, O.J., and Gough, S.C. (2012). Immunogenetic mechanisms leading to thyroid autoimmunity: recent advances in identifying susceptibility genes and regions. Curr Genomics 12, 526- 541.10.2174/138920211798120790
[12] Browne, S.K., and Holland, S.M. (2010). Immunodeficiency secondary to anticytokine autoantibodies. Curr Opin Allergy Clin Immunol 10, 534-541 .10.1097/ACI.0b013e3283402b41
[13] Burrows, S.R., Chen, Z., Archbold, J.K., Tynan, F.E., Beddoe, T., Kjer-Nielsen, L., Miles, J.J., Khanna, R., Moss, D.J., Liu, Y.C., . (2010). Hard wiring of T cell receptor specificity for the major histocompatibility complex is underpinned by TCR adaptability. Proc Natl Acad Sci U S A 107, 10608-10613 .10.1073/pnas.1004926107
[14] Callahan, M.K., Wolchok, J.D., and Allison, J.P. (2010). Anti-CTLA-4 antibody therapy: immune monitoring during clinical development of a novel immunotherapy. Semin Oncol 37, 473-484 .10.1053/j.seminoncol.2010.09.001
[15] Colf, L.A., Bankovich, A.J., Hanick, N.A., Bowerman, N.A., Jones, L.L., Kranz, D.M., and Garcia, K.C. (2007). How a single T cell receptor recognizes both self and foreign MHC. Cell 129, 135-146 .10.1016/j.cell.2007.01.048
[16] Croft, M. (2009). The role of TNF superfamily members in T-cell function and diseases. Nat Rev Immunol 9, 271-285 .10.1038/nri2526
[17] Dai, S., Huseby, E.S., Rubtsova, K., Scott-Browne, J., Crawford, F., Macdonald, W.A., Marrack, P., and Kappler, J.W. (2008). Crossreactive T Cells spotlight the germline rules for alphabeta T cell-receptor interactions with MHC molecules. Immunity 28, 324-334 .10.1016/j.immuni.2008.01.008
[18] Day, E.B., Guillonneau, C., Gras, S., La Gruta, N.L., Vignali, D.A., Doherty, P.C., Purcell, A.W., Rossjohn, J., and Turner, S.J. (2011). Structural basis for enabling T-cell receptor diversity within biased virus-specific CD8+ T-cell responses. Proc Natl Acad Sci U S A 108, 9536-9541 .10.1073/pnas.1106851108
[19] Depaz, R., Granger, B., Cournu-Rebeix, I., Bouafia, A., and Fontaine, B. (2011). Genetics for understanding and predicting clinical progression in multiple sclerosis. Rev Neurol (Paris) 167, 791-801 .10.1016/j.neurol.2011.02.043
[20] Deshmukh, H.A., Maiti, A.K., Kim-Howard, X.R., Rojas-Villarraga, A., Guthridge, J.M., Anaya, J.M., and Nath, S.K. (2011). Evaluation of 19 autoimmune disease-associated loci with rheumatoid arthritis in a Colombian population: evidence for replication and gene-gene interaction. J Rheumatol 38, 1866-1870 .10.3899/jrheum.110199
[21] Dhein, J., Walczak, H., Baumler, C., Debatin, K.M., and Krammer, P.H. (1995). Autocrine T-cell suicide mediated by APO-1/(Fas/CD95). Nature 373, 438-441 .10.1038/373438a0
[22] Dinarello, C.A. (2002). The IL-1 family and inflammatory diseases. Clin Exp Rheumatol 20, S 1-13 .
[23] Dolfi, D.V., and Katsikis, P.D. (2007). CD28 and CD27 costimulation of CD8+ T cells: a story of survival. Adv Exp Med Biol 590, 149-170 .10.1007/978-0-387-34814-8_11
[24] Evnouchidou, I., Birtley, J., Seregin, S., Papakyriakou, A., Zervoudi, E., Samiotaki, M., Panayotou, G., Giastas, P., Petrakis, O., Georgiadis, D., . (2012). A common single nucleotide polymorphism in endoplasmic reticulum aminopeptidase 2 induces a specificity switch that leads to altered antigen processing. J Immunol 189, 2383-2392 .10.4049/jimmunol.1200918
[25] Feng, D., Bond, C.J., Ely, L.K., Maynard, J., and Garcia, K.C. (2007). Structural evidence for a germline-encoded T cell receptor-major histocompatibility complex interaction 'codon'. Nat Immunol 8, 975-983 .10.1038/ni1502
[26] Fierabracci, A., Milillo, A., Locatelli, F., and Fruci, D. (2012). The putative role of endoplasmic reticulum aminopeptidases in autoimmunity: Insights from genomic-wide association studies. Autoimmun Rev . (In Press).10.1016/j.autrev.2012.04.007
[27] Gambineri, E., Torgerson, T.R., and Ochs, H.D. (2003). Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX), a syndrome of systemic autoimmunity caused by mutations of FOXP3, a critical regulator of T-cell homeostasis. Curr Opin Rheumatol 15, 430-435 .10.1097/00002281-200307000-00010
[28] Garcia, K.C., Adams, J.J., Feng, D., and Ely, L.K. (2009). The molecular basis of TCR germline bias for MHC is surprisingly simple. Nat Immunol 10, 143-147 .10.1038/ni.f.219
[29] Garcia, K.C., Degano, M., Pease, L.R., Huang, M., Peterson, P.A., Teyton, L., and Wilson, I.A. (1998). Structural basis of plasticity in T cell receptor recognition of a self peptide-MHC antigen. Science 279, 1166-1172 .10.1126/science.279.5354.1166
[30] Garcia, K.C., Degano, M., Stanfield, R.L., Brunmark, A., Jackson, M.R., Peterson, P.A., Teyton, L., and Wilson, I.A. (1996). An alphabeta T cell receptor structure at 2.5 A and its orientation in the TCR-MHC complex. Science 274, 209-219 .10.1126/science.274.5285.209
[31] Garcia, K.C., Teyton, L., and Wilson, I.A. (1999). Structural basis of T cell recognition. Annu Rev Immunol 17, 369-397 .10.1146/annurev.immunol.17.1.369
[32] Grumet, F.C., Coukell, A., Bodmer, J.G., Bodmer, W.F., and McDevitt, H.O. (1971). Histocompatibility (HL-A) antigens associated with systemic lupus erythematosus. A possible genetic predisposition to disease. N Engl J Med 285, 193-196 .10.1056/NEJM197107222850403
[33] Guerini, F.R., Cagliani, R., Forni, D., Agliardi, C., Caputo, D., Cassinotti, A., Galimberti, D., Fenoglio, C., Biasin, M., Asselta, R., . (2012). A functional variant in ERAP1 predisposes to multiple sclerosis. PLoS One 7, e29931.10.1371/journal.pone.0029931
[34] Hahn, M., Nicholson, M.J., Pyrdol, J., and Wucherpfennig, K.W. (2005). Unconventional topology of self peptide-major histocompatibility complex binding by a human autoimmune T cell receptor. Nat Immunol 6, 490-496 .10.1038/ni1187
[35] Haskins, K., and Cooke, A. (2011). CD4 T cells and their antigens in the pathogenesis of autoimmune diabetes. Curr Opin Immunol 23, 739-745 .10.1016/j.coi.2011.08.004
[36] Heino, M., Peterson, P., Kudoh, J., Shimizu, N., Antonarakis, S.E., Scott, H.S., and Krohn, K. (2001). APECED mutations in the autoimmune regulator (AIRE) gene. Hum Mutat 18, 205-211 .10.1002/humu.1176
[37] Hintzen, R.Q., de Jong, R., Lens, S.M., and van Lier, R.A. (1994). CD27: marker and mediator of T-cell activation? Immunol Today 15, 307-311 .10.1016/0167-5699(94)90077-9
[38] Illing, P.T., Vivian, J.P., Dudek, N.L., Kostenko, L., Chen, Z., Bharadwaj, M., Miles, J.J., Kjer-Nielsen, L., Gras, S., Williamson, N.A., . (2012). Immune self-reactivity triggered by drug-modified HLA-peptide repertoire. Nature 486, 554-558 .
[39] Inaba, K., Metlay, J.P., Crowley, M.T., Witmer-Pack, M., and Steinman, R.M. (1990). Dendritic cells as antigen presenting cells in vivo. Int Rev Immunol 6, 197-206 .10.3109/08830189009056630
[40] Ireland, J.M., and Unanue, E.R. (2012). Processing of proteins in autophagy vesicles of antigen-presenting cells generates citrullinated peptides recognized by the immune system. Autophagy 8, 429-430 .10.4161/auto.19261
[41] Jarchum, I., and DiLorenzo, T.P. (2009). Ins2 deficiency augments spontaneous HLA-A*0201-restricted T cell responses to insulin. J Immunol 184, 658-665 .10.4049/jimmunol.0903414
[42] Jenkins, M.K., and Schwartz, R.H. (1987). Antigen presentation by chemically modified splenocytes induces antigen-specific T cell unresponsiveness in vitro and in vivo. J Exp Med 165, 302-319 .10.1084/jem.165.2.302
[43] Kappler, J.W., Roehm, N., and Marrack, P. (1987). T cell tolerance by clonal elimination in the thymus. Cell 49, 273-280 .10.1016/0092-8674(87)90568-X
[44] Kato, Z., Stern, J.N., Nakamura, H.K., Miyashita, N., Kuwata, K., Kondo, N., and Strominger, J.L. (2010). The autoimmune TCR-Ob.2F3 can bind to MBP85-99/HLA-DR2 having an unconventional mode as in TCR-Ob.1A12. Mol Immunol 48, 314-320 .10.1016/j.molimm.2010.07.010
[45] Kuhn, K.A., Cozine, C.L., Tomooka, B., Robinson, W.H., and Holers, V.M. (2008). Complement receptor CR2/CR1 deficiency protects mice from collagen-induced arthritis and associates with reduced autoantibodies to type II collagen and citrullinated antigens. Mol Immunol 45, 2808-2819 .10.1016/j.molimm.2008.01.036
[46] Lafferty, K.J., and Cunningham, A.J. (1975). A new analysis of allogeneic interactions. Aust J Exp Biol Med Sci 53, 27-42 .10.1038/icb.1975.3
[47] Levisetti, M.G., Suri, A., Petzold, S.J., and Unanue, E.R. (2007). The insulin-specific T cells of nonobese diabetic mice recognize a weak MHC-binding segment in more than one form. J Immunol 178, 6051-6057 .
[48] Li, Y., Huang, Y., Lue, J., Quandt, J.A., Martin, R., and Mariuzza, R.A. (2005). Structure of a human autoimmune TCR bound to a myelin basic protein self-peptide and a multiple sclerosis-associated MHC class II molecule. EMBO J 24, 2968-2979 .10.1038/sj.emboj.7600771
[49] Marrack, P., and Kappler, J.W. (2012). Do MHCII-presented neoantigens drive type 1 diabetes and other autoimmune diseases? Cold Spring Harb Perspect Med 2, a007765.
[50] Marrack, P., Scott-Browne, J.P., Dai, S., Gapin, L., and Kappler, J.W. (2008). Evolutionarily conserved amino acids that control TCR-MHC interaction. Annu Rev Immunol 26, 171-203 .10.1146/annurev.immunol.26.021607.090421
[51] Maynard, J., Petersson, K., Wilson, D.H., Adams, E.J., Blondelle, S.E., Boulanger, M.J., Wilson, D.B., and Garcia, K.C. (2005). Structure of an autoimmune T cell receptor complexed with class II peptide-MHC: insights into MHC bias and antigen specificity. Immunity 22, 81-92 .
[52] McDevitt, H.O., and Bodmer, W.F. (1974). HL-A, immune-response genes, and disease. Lancet 1, 1269-1275 .10.1016/S0140-6736(74)90021-X
[53] Mohan, J.F., Levisetti, M.G., Calderon, B., Herzog, J.W., Petzold, S.J., and Unanue, E.R. (2010). Unique autoreactive T cells recognize insulin peptides generated within the islets of Langerhans in autoimmune diabetes. Nat Immunol 11, 350-354 .10.1038/ni.1850
[54] Nakayama, M., Beilke, J.N., Jasinski, J.M., Kobayashi, M., Miao, D., Li, M., Coulombe, M.G., Liu, E., Elliott, J.F., Gill, R.G., . (2007). Priming and effector dependence on insulin B:9-23 peptide in NOD islet autoimmunity. J Clin Invest 117, 1835-1843 .10.1172/JCI31368
[55] Pardoll, D.M. (2012). The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12, 252-264 .10.1038/nrc3239
[56] Rainbow, D.B., Esposito, L., Howlett, S.K., Hunter, K.M., Todd, J.A., Peterson, L.B., and Wicker, L.S. (2008). Commonality in the genetic control of Type 1 diabetes in humans and NOD mice: variants of genes in the IL-2 pathway are associated with autoimmune diabetes in both species. Biochem Soc Trans 36, 312-315 .10.1042/BST0360312
[57] Ramsdell, F. (2003). Foxp3 and natural regulatory T cells: key to a cell lineage? Immunity 19, 165-168 .10.1016/S1074-7613(03)00207-3
[58] Ramsey, C., Winqvist, O., Puhakka, L., Halonen, M., Moro, A., Kampe, O., Eskelin, P., Pelto-Huikko, M., and Peltonen, L. (2002). Aire deficient mice develop multiple features of APECED phenotype and show altered immune response. Hum Mol Genet 11, 397-409 .10.1093/hmg/11.4.397
[59] Reiser, J.B., Darnault, C., Gregoire, C., Mosser, T., Mazza, G., Kearney, A., van der Merwe, P.A., Fontecilla-Camps, J.C., Housset, D., and Malissen, B. (2003). CDR3 loop flexibility contributes to the degeneracy of TCR recognition. Nat Immunol 4, 241-247 .10.1038/ni891
[60] Rubin, B., and Sonderstrup, G. (2004). Citrullination of self-proteins and autoimmunity. Scand J Immunol 60, 112-120 .10.1111/j.0300-9475.2004.01457.x
[61] Sethi, D.K., Schubert, D.A., Anders, A.K., Heroux, A., Bonsor, D.A., Thomas, C.P., Sundberg, E.J., Pyrdol, J., and Wucherpfennig, K.W. (2011). A highly tilted binding mode by a self-reactive T cell receptor results in altered engagement of peptide and MHC. J Exp Med 208, 91-102 .10.1084/jem.20100725
[62] Sharpe, A.H. (2009). Mechanisms of costimulation. Immunol Rev 229, 5-11 .10.1111/j.1600-065X.2009.00784.x
[63] Sloan-Lancaster, J., and Allen, P.M. (1995). Signalling events in the anergy induction of T helper 1 cells. Ciba Found Symp 195, 189-196 ; discussion 196-202 .
[64] Sneller, M.C., Wang, J., Dale, J.K., Strober, W., Middelton, L.A., Choi, Y., Fleisher, T.A., Lim, M.S., Jaffe, E.S., Puck, J.M., . (1997). Clincal, immunologic, and genetic features of an autoimmune lymphoproliferative syndrome associated with abnormal lymphocyte apoptosis. Blood 89, 1341-1348 .
[65] Stadinski, B.D., Delong, T., Reisdorph, N., Reisdorph, R., Powell, R.L., Armstrong, M., Piganelli, J.D., Barbour, G., Bradley, B., Crawford, F., . (2010a). Chromogranin A is an autoantigen in type 1 diabetes. Nat Immunol 11, 225-231 .10.1038/ni.1844
[66] Stadinski, B.D., Zhang, L., Crawford, F., Marrack, P., Eisenbarth, G.S., and Kappler, J.W. (2010b). Diabetogenic T cells recognize insulin bound to IAg7 in an unexpected, weakly binding register. Proc Natl Acad Sci U S A 107, 10978-10983 .10.1073/pnas.1006545107
[67] Steinman, R.M., and Inaba, K. (1985). Stimulation of the primary mixed leukocyte reaction. Crit Rev Immunol 5, 331-348 .
[68] Steinman, R.M., Koide, S., Witmer, M., Crowley, M., Bhardwaj, N., Freudenthal, P., Young, J., and Inaba, K. (1988). The sensitization phase of T-cell-mediated immunity. Ann N Y Acad Sci 546, 80-90 .10.1111/j.1749-6632.1988.tb21622.x
[69] Suri, A., Levisetti, M.G., and Unanue, E.R. (2008). Do the peptide-binding properties of diabetogenic class II molecules explain autoreactivity? Curr Opin Immunol 20, 105-110 .10.1016/j.coi.2007.10.007
[70] Tynan, F.E., Burrows, S.R., Buckle, A.M., Clements, C.S., Borg, N.A., Miles, J.J., Beddoe, T., Whisstock, J.C., Wilce, M.C., Silins, S.L., . (2005). T cell receptor recognition of a 'super-bulged' major histocompatibility complex class I-bound peptide. Nat Immunol 6, 1114-1122 .10.1038/ni1257
[71] Tynan, F.E., Reid, H.H., Kjer-Nielsen, L., Miles, J.J., Wilce, M.C., Kostenko, L., Borg, N.A., Williamson, N.A., Beddoe, T., Purcell, A.W., . (2007). A T cell receptor flattens a bulged antigenic peptide presented by a major histocompatibility complex class I molecule. Nat Immunol 8, 268-276 .10.1038/ni1432
[72] van Boekel, M.A., Vossenaar, E.R., van den Hoogen, F.H., and van Venrooij, W.J. (2002). Autoantibody systems in rheumatoid arthritis: specificity, sensitivity and diagnostic value. Arthritis Res 4, 87-93 .10.1186/ar395
[73] von Boehmer, H., Teh, H.S., and Kisielow, P. (1989). The thymus selects the useful, neglects the useless and destroys the harmful. Immunol Today 10, 57-61 .10.1016/0167-5699(89)90307-1
[74] Watts, T.H. (2010). Staying alive: T cell costimulation, CD28, and Bcl-xL. J Immunol 185, 3785-3787 .10.4049/jimmunol.1090085
[75] Wherry, E.J., Ha, S.J., Kaech, S.M., Haining, W.N., Sarkar, S., Kalia, V., Subramaniam, S., Blattman, J.N., Barber, D.L., and Ahmed, R. (2007). Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27, 670-684 .10.1016/j.immuni.2007.09.006
[76] Wildin, R.S., Smyk-Pearson, S., and Filipovich, A.H. (2002). Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. J Med Genet 39, 537-545 .10.1136/jmg.39.8.537
[77] Yin, L., Crawford,F., Marrack, P., Kappler, J.W. and Dai, S. (2012b) T-cell receptor (TCR) interaction with peptides that mimic nickel offers insight into nickel contact allergy. Proc Natl Acad Sci U S A 109, 18517-18522 .10.1073/pnas.1215928109
[78] Yin, L., Huseby, E., Scott-Browne, J., Rubtsova, K., Pinilla, C., Crawford, F., Marrack, P., Dai, S., and Kappler, J.W. (2011a). A single T cell receptor bound to major histocompatibility complex class I and class II glycoproteins reveals switchable TCR conformers. Immunity 35, 23-33 .10.1016/j.immuni.2011.04.017
[79] Yin, Y., Li, Y., Kerzic, M.C., Martin, R., and Mariuzza, R.A. (2011b). Structure of a TCR with high affinity for self-antigen reveals basis for escape from negative selection. EMBO J 30, 1137-1148 .10.1038/emboj.2011.21
[80] Yin, Y., Wang, X.X., and Mariuzza, R.A. (2012a). Crystal structure of a complete ternary complex of T-cell receptor, peptide-MHC, and CD4. Proc Natl Acad Sci U S A 109, 5405-5410 .10.1073/pnas.1118801109