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HLA variation and disease

Key Points

  • Five decades since the first description of an HLA association with disease, the HLA molecule has been demonstrated to be central to physiology, protective immunity and deleterious immune reactivity.

  • The specificity of HLA–peptide–T cell receptor (TCR) tripartite interactions is fundamental in enabling the adaptive immune system to mount an efficient and appropriate response to counteract infection and malignancy while maintaining self tolerance and preventing autoimmune disease.

  • Understanding the molecular principles that govern these interactions — so as to distil them into mechanistic insight regarding the role of HLA in driving and protecting against immunopathology — presents an ongoing biomedical research challenge but also holds much therapeutic promise.

  • The molecular mechanisms identified to date that influence HLA–peptide–TCR interactions and that have been implicated in autoimmune disease development include alternate TCR docking, low-affinity-mediated thymic escape, TCR stabilization of weak peptide–HLA complexes, altered binding registers, 'hotspot' molecular mimicry, post-translational modification of antigenic peptides, hybrid peptides and differential HLA expression and stability.

  • The identification of these numerous molecular mechanisms represents the outcome of several key technological advances in genetics, genomics, statistics, computational biology, peptide–HLA tetramer use for T cell repertoire interrogation and epitope mapping, structural biology and transgenics.

  • The progress in characterizing HLA diversity, HLA associations with human disease and HLA–peptide–receptor interactions and their mechanistic implications has galvanized efforts to harness the improved understanding of HLA function for clinical benefit, leading to the development and trialling of antigen-specific therapies that include vaccination and a range of other noncellular disease prevention strategies and therapies as well as cell-based therapeutic approaches.

Abstract

Fifty years since the first description of an association between HLA and human disease, HLA molecules have proven to be central to physiology, protective immunity and deleterious, disease-causing autoimmune reactivity. Technological advances have enabled pivotal progress in the determination of the molecular mechanisms that underpin the association between HLA genetics and functional outcome. Here, we review our current understanding of HLA molecules as the fundamental platform for immune surveillance and responsiveness in health and disease. We evaluate the scope for personalized antigen-specific disease prevention, whereby harnessing HLA–ligand interactions for clinical benefit is becoming a realistic prospect.

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Figure 1: HLA-dependent molecular mechanisms of peptide and T cell receptor binding.
Figure 2: HLA–peptide–T cell receptor interactions can promote autoimmunity.

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References

  1. Amiel, J. in Study of the Leukocyte Phenotypes in Hodgkin's Disease in Histocompatibility Testing (ed. Teraski, P. I.) 79–81 (Munksgaard, 1967).

    Google Scholar 

  2. Trowsdale, J. & Knight, J. C. Major histocompatibility complex genomics and human disease. Ann. Rev. Genom. Hum. Genet. 14, 301–323 (2013).

    Article  CAS  Google Scholar 

  3. Godfrey, D. I., Uldrich, A. P., McCluskey, J., Rossjohn, J. & Moody, D. B. The burgeoning family of unconventional T cells. Nat. Immunol. 16, 1114–1123 (2015).

    Article  CAS  PubMed  Google Scholar 

  4. Robinson, J., Soormally, A. R., Hayhurst, J. D. & Marsh, S. G. E. The IPD-IMGT/HLA database — new developments in reporting HLA variation. Hum. Immunol. 77, 233–237 (2016).

    Article  CAS  PubMed  Google Scholar 

  5. Parham, P. & Ohta, T. Population biology of antigen presentation by MHC class I molecules. Science 272, 67–74 (1996).

    Article  CAS  PubMed  Google Scholar 

  6. Carrington, M. et al. HLA and HIV-1: heterozygote advantage and B*35-Cw*04 disadvantage. Science 283, 1748–1752 (1999).

    Article  CAS  PubMed  Google Scholar 

  7. Parham, P. & Moffett, A. Variable NK cell receptors and their MHC class I ligands in immunity, reproduction and human evolution. Nat. Rev. Immunol. 13, 133–144 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Sewell, A. K. Why must T cells be cross-reactive? Nat. Rev. Immunol. 12, 668–677 (2012).

    Article  CAS  Google Scholar 

  9. Quigley, M. F. et al. Convergent recombination shapes the clonotypic landscape of the naive T-cell repertoire. Proc. Natl Acad. Sci. USA 107, 19414–19419 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Saunders, P. M. et al. A bird's eye view of NK cell receptor interactions with their MHC class I ligands. Immunol. Rev. 267, 148–166 (2015).

    Article  CAS  PubMed  Google Scholar 

  11. Hudson, L. E. & Allen, R. L. Leukocyte Ig-Like Receptors — a model for MHC class I disease associations. Front. Immunol. 7, 281 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Fadda, L. et al. Peptide antagonism as a mechanism for NK cell activation. Proc. Natl Acad. Sci. USA 107, 10160–10165 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Sim, M. J. et al. Canonical and cross-reactive binding of NK cell inhibitory receptors to HLA-C allotypes is dictated by peptides bound to HLA-C. Front. Immunol. 8, 193 (2017).

    PubMed  PubMed Central  Google Scholar 

  14. Miles, J. J., McCluskey, J., Rossjohn, J. & Gras, S. Understanding the complexity and malleability of T-cell recognition. Immunol. Cell Biol. 93, 433–441 (2015).

    Article  CAS  PubMed  Google Scholar 

  15. Madsen, L. S. et al. A humanized model for multiple sclerosis using HLA-DR2 and a human T-cell receptor. Nat. Genet. 23, 343–347 (1999).

    Article  CAS  PubMed  Google Scholar 

  16. Hahn, M., Nicholson, M. J., Pyrdol, J. & Wucherpfennig, K. W. Unconventional topology of self peptide-major histocompatibility complex binding by a human autoimmune T cell receptor. Nat. Immunol. 6, 490–496 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Bulek, A. M. et al. Structural basis for the killing of human beta cells by CD8+ T cells in type 1 diabetes. Nat. Immunol. 13, 283–289 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Pugliese, A. et al. The insulin gene is transcribed in the human thymus and transcription levels correlate with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes. Nat. Genet. 15, 293–297 (1997).

    Article  CAS  PubMed  Google Scholar 

  19. Cole, D. K. et al. Hotspot autoimmune T cell receptor binding underlies pathogen and insulin peptide cross-reactivity. J. Clin. Invest. 126, 2191–2204 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Yin, Y., Li, Y., Kerzic, M. C., Martin, R. & Mariuzza, R. A. Structure of a TCR with high affinity for self-antigen reveals basis for escape from negative selection. EMBO J. 30, 1137–1148 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Quandt, J. A. et al. Unique clinical and pathological features in HLA-DRB1*0401-restricted MBP 111-129-specific humanized TCR transgenic mice. J. Exp. Med. 200, 223–234 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Armstrong, K. M., Piepenbrink, K. H. & Baker, B. M. Conformational changes and flexibility in T-cell receptor recognition of peptide-MHC complexes. Biochem. J. 415, 183–196 (2008).

    Article  PubMed  CAS  Google Scholar 

  23. Stadinski, B. D. et al. Diabetogenic T cells recognize insulin bound to IAg7 in an unexpected, weakly binding register. Proc. Natl Acad. Sci. USA 107, 10978–10983 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Yang, J. et al. Autoreactive T cells specific for insulin B:11-23 recognize a low-affinity peptide register in human subjects with autoimmune diabetes. Proc. Natl Acad. Sci. USA 111, 14840–14845 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ooi, J. D. et al. Dominant protection from HLA-linked autoimmunity by antigen-specific regulatory T cells. Nature 545, 243–247 (2017). This study reveals a mechanistic basis for the dominantly protective effect of HLA in autoimmune disease via an effect on self-epitope-specific T reg cells.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Harkiolaki, M. et al. T cell-mediated autoimmune disease due to low-affinity crossreactivity to common microbial peptides. Immunity 30, 348–357 (2009).

    Article  CAS  PubMed  Google Scholar 

  27. Sethi, D. K. et al. 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 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Wucherpfennig, K. W. & Strominger, J. L. Molecular mimicry in T cell-mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein. Cell 80, 695–705 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Belbasis, L., Bellou, V., Evangelou, E., Ioannidis, J. P. A. & Tzoulaki, L. Environmental risk factors and multiple sclerosis: an umbrella review of systematic reviews and meta-analyses. Lancet Neurol. 14, 263–273 (2015).

    Article  PubMed  Google Scholar 

  30. Moutsianas, L. et al. Class II HLA interactions modulate genetic risk for multiple sclerosis. Nat. Genet. 47, 1107–1113 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Nielsen, T. R. et al. Effects of infectious mononucleosis and HLA-DRB1*15 in multiple sclerosis. Mult. Scler. J. 15, 431–436 (2009).

    Article  CAS  Google Scholar 

  32. Lang, H. L. E. et al. A functional and structural basis for TCR cross-reactivity in multiple sclerosis. Nat. Immunol. 3, 940–943 (2002).

    Article  CAS  PubMed  Google Scholar 

  33. Babon, J. A. et al. Analysis of self-antigen specificity of islet-infiltrating T cells from human donors with type 1 diabetes. Nat. Med. 22, 1482–1487 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Koning, F., Thomas, R., Rossjohn, J. & Toes, R. E. Coeliac disease and rheumatoid arthritis: similar mechanisms, different antigens. Nat. Rev. Rheumatol. 11, 450–461 (2015).

    Article  CAS  PubMed  Google Scholar 

  35. Scally, S. W. et al. A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis. J. Exp. Med. 210, 2569–2582 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Mohammed, F. et al. Phosphorylation-dependent interaction between antigenic peptides and MHC class I: a molecular basis for the presentation of transformed self. Nat. Immunol. 9, 1236–1243 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Mannering, S. I. et al. The insulin A-chain epitope recognized by human T cells is posttranslationally modified. J. Exp. Med. 202, 1191–1197 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Molberg, O. et al. Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nat. Med. 4, 713–717 (1998).

    Article  CAS  PubMed  Google Scholar 

  39. Bodd, M., Kim, C. Y., Lundin, K. E. & Sollid, L. M. T-Cell response to gluten in patients with HLA-DQ2.2 reveals requirement of peptide-MHC stability in celiac disease. Gastroenterology 142, 552–561 (2012).

    Article  CAS  PubMed  Google Scholar 

  40. Fallang, L. E. et al. Differences in the risk of celiac disease associated with HLA-DQ2.5 or HLA-DQ2.2 are related to sustained gluten antigen presentation. Nat. Immunol. 10, 1096–1101 (2009).

    Article  CAS  PubMed  Google Scholar 

  41. Hovhannisyan, Z. et al. The role of HLA-DQ8 β57 polymorphism in the anti-gluten T-cell response in coeliac disease. Nature 456, 534–538 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Todd, J. A., Bell, J. I. & McDevitt, H. O. HLA-DQ-β gene contributes to susceptibility and resistance to insulin-dependent diabetes-mellitus. Nature 329, 599–604 (1987).

    Article  CAS  PubMed  Google Scholar 

  43. Corper, A. L. et al. A structural framework for deciphering the link between I-Ag7 and autoimmune diabetes. Science 288, 505–511 (2000).

    Article  CAS  PubMed  Google Scholar 

  44. Broughton, S. E. et al. Biased T cell receptor usage directed against human leukocyte antigen DQ8-restricted gliadin peptides is associated with celiac disease. Immunity 37, 611–621 (2012).

    Article  CAS  PubMed  Google Scholar 

  45. Petersen, J. et al. T-Cell receptor recognition of HLA-DQ2-gliadin complexes associated with celiac disease. Nat. Struct. Mol. Biol. 21, 480–488 (2014).

    Article  CAS  PubMed  Google Scholar 

  46. Dieterich, W. et al. Identification of tissue transglutaminase as the autoantigen of celiac disease. Nat. Med. 3, 797–801 (1997).

    Article  CAS  PubMed  Google Scholar 

  47. Verpoort, K. N. et al. Isotype distribution of anti-cyclic citrullinated peptide antibodies in undifferentiated arthritis and rheumatoid arthritis reflects an ongoing immune response. Arthritis Rheum. 54, 3799–3808 (2006).

    Article  CAS  PubMed  Google Scholar 

  48. Liepe, J. et al. A large fraction of HLA class I ligands are proteasome-generated spliced peptides. Science 354, 354–358 (2016). This study demonstrates that the proteasome-generated hybrid peptide pool accounts for as much as one-third of the HLA class I immunopeptidome, with implications for disease mechanisms and antigen-specific therapies.

    Article  CAS  PubMed  Google Scholar 

  49. Hansen, T. H. & Bouvier, M. MHC class I antigen presentation: learning from viral evasion strategies. Nat. Rev. Immunol. 9, 503–513 (2009).

    Article  CAS  PubMed  Google Scholar 

  50. Jin, N. et al. N-Terminal additions to the WE14 peptide of chromogranin A create strong autoantigen agonists in type 1 diabetes. Proc. Natl Acad. Sci. USA 112, 13318–13323 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Delong, T. et al. Pathogenic CD4 T cells in type 1 diabetes recognize epitopes formed by peptide fusion. Science 351, 711–714 (2016). This study demonstrates that hybrid insulin peptides can be found in pancreatic islet β-cells in T1D and are antigenic for CD4+ T cells.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Raj, P. et al. Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity. eLife 5, e12089 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. O'Huigin, C. et al. The molecular origin and consequences of escape from miRNA regulation by HLA-C alleles. Am. J. Hum. Genet. 89, 424–431 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Shrestha, D., Szollosi, J. & Jenei, A. Bare lymphocyte syndrome: an opportunity to discover our immune system. Immunol. Lett. 141, 147–157 (2012).

    Article  CAS  PubMed  Google Scholar 

  55. Rowe, M. et al. Host shutoff during productive Epstein–Barr virus infection is mediated by BGLF5 and may contribute to immune evasion. Proc. Natl Acad. Sci. USA 104, 3366–3371 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Balan, N., Osborn, K. & Sinclair, A. J. Repression of CIITA by the Epstein–Barr virus transcription factor Zta is independent of its dimerization and DNA binding. J. Gen. Virol. 97, 725–732 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Petersdorf, E. W. et al. HLA-C expression levels define permissible mismatches in hematopoietic cell transplantation. Blood 124, 3996–4003 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Petersdorf, E. W. et al. High HLA-DP expression and graft-versus-host disease. N. Engl. J. Med. 373, 599–609 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Ferreira, L. M. R., Meissner, T. B., Tilburgs, T. & Strominger, J. L. HLA-G: at the interface of maternal-fetal tolerance. Trends Immunol. 38, 272–286 (2017).

    Article  CAS  PubMed  Google Scholar 

  60. Quach, K., Grover, S. A., Kenigsberg, S. & Librach, C. L. A combination of single nucleotide polymorphisms in the 3′ untranslated region of HLA-G is associated with preeclampsia. Hum. Immunol. 75, 1163–1170 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Ljunggren, H. G. et al. Empty MHC class-I molecules come out in the cold. Nature 346, 476–480 (1990).

    Article  CAS  PubMed  Google Scholar 

  62. Wearsch, P. A. & Cresswell, P. Selective loading of high-affinity peptides onto major histocompatibility complex class I molecules by the tapasin-ERp57 heterodimer. Nat. Immunol. 8, 873–881 (2007).

    Article  CAS  PubMed  Google Scholar 

  63. Williams, A. P., Peh, C. A., Purcell, A. W., McCluskey, J. & Elliott, T. Optimization of the MHC class I peptide cargo is dependent on tapasin. Immunity 16, 509–520 (2002).

    Article  CAS  PubMed  Google Scholar 

  64. Rizvi, S. M. et al. Distinct assembly profiles of HLA-B molecules. J. Immunol. 192, 4967–4976 (2014).

    Article  PubMed  CAS  Google Scholar 

  65. Thammavongsa, V., Raghuraman, G., Filzen, T. M., Collins, K. L. & Raghavan, M. HLA-B44 polymorphisms at position 116 of the heavy chain influence TAP complex minding via an effect on peptide occupancy. J. Immunol. 177, 3150–3161 (2006).

    Article  CAS  PubMed  Google Scholar 

  66. Zernich, D. et al. Natural HLA class I polymorphism controls the pathway of antigen presentation and susceptibility to viral evasion. J. Exp. Med. 200, 13–24 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Apps, R. et al. Relative expression levels of the HLA class-I proteins in normal and HIV-infected cells. J. Immunol. 194, 3594–3600 (2015).

    Article  PubMed  CAS  Google Scholar 

  68. Kaur, G. et al. Structural and regulatory diversity shape HLA-C protein expression levels. Nat. Commun. 8, 15924 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Horowitz, A. et al. Class I HLA haplotypes form two schools that educate NK cells in different ways. Sci. Immunol. 1, eaag1672 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Duggal, P. et al. Genome-wide association study of spontaneous resolution of hepatitis C virus infection: data from multiple cohorts. Ann. Intern. Med. 158, 235–245 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Miyadera, H., Ohashi, J., Lernmark, Å., Kitamura, T. & Tokunaga, K. Cell-surface MHC density profiling reveals instability of autoimmunity-associated HLA. J. Clin. Invest. 125, 275–291 (2015).

    Article  PubMed  Google Scholar 

  72. Zhou, Z. & Jensen, P. E. Structural characteristics of HLA-DQ that may impact DM editing and susceptibility to type-1 diabetes. Front. Immunol. 4, 262 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Ferreira, R. C. et al. High-density SNP mapping of the HLA region identifies multiple independent susceptibility loci associated with selective IgA deficiency. PLOS Genet. 8, e1002476 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Weinstock, C. et al. Autoimmune polyglandular syndrome type 2 shows the same HLA class II pattern as type 1 diabetes. Tissue Antigens 77, 317–324 (2011).

    Article  CAS  PubMed  Google Scholar 

  75. Hu, X. L. et al. Additive and interaction effects at three amino acid positions in HLA-DQ and HLA-DR molecules drive type 1 diabetes risk. Nat. Genet. 47, 898–905 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Mignot, E. et al. Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups. Am. J. Hum. Genet. 68, 686–699 (2001).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Cortes, A. et al. Bayesian analysis of genetic association across tree-structured routine healthcare data in the UK Biobank. Nat. Genet. 49, 1311–1318 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. McGonagle, D., Aydin, S. Z., Gul, A., Mahr, A. & Direskeneli, H. 'MHC-I-opathy'-unified concept for spondyloarthritis and Behcet disease. Nat. Rev. Rheumatol. 11, 731–740 (2015).

    Article  CAS  PubMed  Google Scholar 

  79. Brown, M. A., Kenna, T. & Wordsworth, B. P. Genetics of ankylosing spondylitis — insights into pathogenesis. Nat. Rev. Rheumatol. 12, 81–91 (2016).

    Article  CAS  PubMed  Google Scholar 

  80. Lenz, T. L. et al. Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases. Nat. Genet. 47, 1085–1090 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Vader, W. et al. The HLA-DQ2 gene dose effect in celiac disease is directly related to the magnitude and breadth of gluten-specific T cell responses. Proc. Natl Acad. Sci. USA 100, 12390–12395 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Gregersen, J. W. et al. Functional epistasis on a common MHC haplotype associated with multiple sclerosis. Nature 443, 574–577 (2006).

    Article  CAS  PubMed  Google Scholar 

  83. Sulzer, D. et al. T cells from patients with Parkinson's disease recognize α-synuclein peptides. Nature 546, 656–661 (2017). This study demonstrates that the HLA associations with Parkinson disease may be related to the presence of α -synuclein-specific T cells, suggesting a relevance of the immune system in this neurodegenerative condition.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Tan, A. T. et al. Host ethnicity and virus genotype shape the hepatitis B virus-specific T-cell repertoire. J. Virol. 82, 10986–10997 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Ansari, M. A. et al. Genome-to-genome analysis highlights the effect of the human innate and adaptive immune systems on the hepatitis C virus. Nat. Genet, 49, 666–673 (2017).

    Article  CAS  Google Scholar 

  86. Swadling, L. et al. A human vaccine strategy based on chimpanzee adenoviral and MVA vectors that primes, boosts, and sustains functional HCV-specific T cell memory. Sci. Transl. Med. 6, 261ra153 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Park, S. H. et al. Subinfectious hepatitis C virus exposures suppress T cell responses against subsequent acute infection. Nat. Med. 19, 1638–1642 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Shukla, S. A. et al. Comprehensive analysis of cancer-associated somatic mutations in class I HLA genes. Nat. Biotechnol. 33, 1152–1158 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. McGranahan, N. et al. Allele-specific HLA loss and immune escape in lung cancer evolution. Cell 171, 1259–1271.e11 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Marty, R. et al. MHC-1 genotype restricts the oncogenic mutational landscape. Cell 171, 1272–1283.e15 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Vanderlugt, C. L. & Miller, S. D. Epitope spreading in immune-mediated diseases: implications for immunotherapy. Nat. Rev. Immunol. 2, 85–95 (2002).

    Article  CAS  PubMed  Google Scholar 

  92. Vader, W. et al. The gluten response in children with celiac disease is directed toward multiple gliadin and glutenin peptides. Gastroenterology 122, 1729–1737 (2002).

    Article  CAS  PubMed  Google Scholar 

  93. Altman, J. D. et al. Phenotypic analysis of antigen-specific T lymphocytes. Science 274, 94–96 (1996).

    Article  CAS  PubMed  Google Scholar 

  94. Dolton, G. et al. Comparison of peptide-major histocompatibility complex tetramers and dextramers for the identification of antigen-specific T cells. Clin. Exp. Immunol. 177, 47–63 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Nepom, G. T. MHC class II tetramers. J. Immunol. 188, 2477–2482 (2012).

    Article  PubMed  CAS  Google Scholar 

  96. Newell, E. W. et al. Combinatorial tetramer staining and mass cytometry analysis facilitate T-cell epitope mapping and characterization. Nat. Biotechnol. 31, 623–629 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Glanville, J. et al. Identifying specificity groups in the T cell receptor repertoire. Nature 547, 94–98 (2017). This study describes the development of an algorithm for analysing large numbers of TCR sequences and defining TCR specificity groups across TCRs and individuals, which may facilitate analyses of T cell responses and ligand identification.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Stubbington, M. J. et al. T cell fate and clonality inference from single-cell transcriptomes. Nat. Methods 13, 329–332 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Stadinski, B. D. et al. Hydrophobic CDR3 residues promote the development of self-reactive T cells. Nat. Immunol. 17, 946–955 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Birnbaum, M. E. et al. Deconstructing the peptide-MHC specificity of T cell recognition. Cell 157, 1073–1087 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Borbulevych, O. Y., Santhanagopolan, S. M., Hossain, M. & Baker, B. M. TCRs used in cancer gene therapy cross-react with MART-1/Melan-A tumor antigens via distinct mechanisms. J. Immunol. 187, 2453–2463 (2011).

    Article  PubMed  CAS  Google Scholar 

  102. Hansen, S. G. et al. Cytomegalovirus vectors violate CD8+ T cell epitope recognition paradigms. Science 340, 1237874 (2013).

    Article  CAS  PubMed  Google Scholar 

  103. Beringer, D. X. et al. T cell receptor reversed polarity recognition of a self-antigen major histocompatibility complex. Nat. Immunol. 16, 1153–1161 (2015).

    Article  CAS  PubMed  Google Scholar 

  104. Gras, S. et al. Reversed T cell receptor docking on a major histocompatibility class I complex limits involvement in the immune response. Immunity 45, 749–760 (2016).

    Article  CAS  PubMed  Google Scholar 

  105. RTS,S Clinical Trials Partnership. Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. Lancet 386, 31–45 (2015).

  106. Henao-Restrepo, A. M. et al. Efficacy and effectiveness of an rVSV-vectored vaccine expressing Ebola surface glycoprotein: interim results from the Guinea ring vaccination cluster-randomised trial. Lancet 386, 857–866 (2015).

    Article  CAS  PubMed  Google Scholar 

  107. Hadinegoro, S. R. et al. Efficacy and long-term safety of a Dengue vaccine in regions of endemic disease. N. Engl. J. Med. 373, 1195–1206 (2015).

    Article  CAS  PubMed  Google Scholar 

  108. Plotkin, S. A. The pertussis problem. Clin. Infect. Dis. 58, 830–833 (2014).

    Article  PubMed  Google Scholar 

  109. Ovsyannikova, I. G., Dhiman, N., Jacobson, R. M. & Poland, G. A. Human leukocyte antigen polymorphisms: variable humoral immune responses to viral vaccines. Expert Rev. Vaccines 5, 33–43 (2006).

    Article  CAS  PubMed  Google Scholar 

  110. Bomfim, I. L. et al. The immunogenetics of narcolepsy associated with A(H1N1)pdm09 vaccination (Pandemrix) supports a potent gene-environment interaction. Genes Immun. 18, 75–81 (2017).

    Article  CAS  PubMed  Google Scholar 

  111. Tavira, B. et al. Effect of simultaneous vaccination with H1N1 and GAD-alum on GAD65-induced immune response. Diabetologia 60, 1276–1283 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Larche, M. & Wraith, D. C. Peptide-based therapeutic vaccines for allergic and autoimmune diseases. Nat. Med. 11, S69–S76 (2005).

    Article  CAS  PubMed  Google Scholar 

  113. Alhadj Ali, M. et al. Metabolic and immune effects of immunotherapy with proinsulin peptide in human new-onset type 1 diabetes. Sci. Transl. Med. 9, eaaf7779 (2017).

    Article  CAS  PubMed  Google Scholar 

  114. Afridi, S., Hoessli, D. C. & Hameed, M. W. Mechanistic understanding and significance of small peptides interaction with MHC class II molecules for therapeutic applications. Immunol. Rev. 272, 151–168 (2016).

    Article  CAS  PubMed  Google Scholar 

  115. Ludvigsson, J., Wahlberg, J. & Casas, R. Intralymphatic injection of autoantigen in type 1 diabetes. N. Engl. J. Med. 376, 697–699 (2017).

    Article  PubMed  Google Scholar 

  116. Clemente-Casares, X. et al. Expanding antigen-specific regulatory networks to treat autoimmunity. Nature 530, 434–440 (2016). This study demonstrates that systemic delivery of nanoparticles coated with autoimmune-disease-relevant peptides bound to MHC class II molecules can trigger the generation and expansion of antigen-specific regulatory CD4+ T cells, with potential therapeutic implications.

    Article  CAS  PubMed  Google Scholar 

  117. Pitt, J. M. et al. Dendritic cell-derived exosomes for cancer therapy. J. Clin. Invest. 126, 1224–1232 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Liddy, N. et al. Monoclonal TCR-redirected tumor cell killing. Nat. Med. 18, 980–987 (2012).

    Article  CAS  PubMed  Google Scholar 

  119. Bluestone, J. A. et al. Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci. Transl. Med. 7, 315ra189 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Chandran, S. et al. Polyclonal regulatory T cell therapy for control of inflammation in kidney transplants. Am. J. Transplant. 17, 2945–2954 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Verdegaal, E. M. E. et al. Neoantigen landscape dynamics during human melanoma-T cell interactions. Nature 536, 91–95 (2016).

    Article  CAS  PubMed  Google Scholar 

  122. Stronen, E. et al. Targeting of cancer neoantigens with donor-derived T cell receptor repertoires. Science 352, 1337–1341 (2016). This study demonstrates that a higher frequency of tumour mutations is more immunogenic than initially estimated and that healthy donors can be a valuable source of T cells that are reactive to these tumour neoantigens, thereby indicating a new, personalized approach for cancer immunotherapy.

    Article  CAS  PubMed  Google Scholar 

  123. de Bakker, P. I. W. et al. A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC. Nat. Genet. 38, 1166–1172 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Dilthey, A., Cox, C., Iqbal, Z., Nelson, M. R. & McVean, G. Improved genome inference in the MHC using a population reference graph. Nat. Genet. 47, 682–688 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Raychaudhuri, S. et al. Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat. Genet. 44, 291–296 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Zhou, F. S. et al. Deep sequencing of the MHC region in the Chinese population contributes to studies of complex disease. Nat. Genet. 48, 740–746 (2016).

    Article  CAS  PubMed  Google Scholar 

  127. Dolton, G. et al. More tricks with tetramers: a practical guide to staining T cells with peptide-MHC multimers. Immunology 146, 11–22 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  128. Sabatino, J. J. Jr, Huang, J., Zhu, C. & Evavold, B. D. High prevalence of low affinity peptide-MHC II tetramer-negative effectors during polyclonal CD4+ T cell responses. J. Exp. Med. 208, 81–90 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Wekerle, H., Flugel, A., Fugger, L., Schett, G. & Serreze, D. Autoimmunity's next top models. Nat. Med. 18, 66–70 (2012).

    Article  CAS  PubMed  Google Scholar 

  130. Yu, D. et al. Roquin represses autoimmunity by limiting inducible T-cell co-stimulator messenger RNA. Nature 450, 299–303 (2007).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

C.A.D. is supported by the Wellcome Centre and the Royal Society. J.R. is supported by grants from the National Health and Medical Research Council (Australia), the Cancer Council of Victoria, the Australian Research Council (ARC) and Worldwide Cancer Research and is an ARC Laureate Fellow. L.F. is supported by the Wellcome Centre, the Medical Research Council, the Danish National Research Foundation, Takeda and the Oak Foundation.

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C.A.D. and J.R. researched data for the article; L.F., C.A.D., J.R. and L.F. had a substantial input into the discussion of content; C.A.D., J.R and L.F. wrote the article; and L.F. and C.A.D. carried out the review and editing.

Corresponding authors

Correspondence to Jamie Rossjohn or Lars Fugger.

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The authors declare no competing financial interests.

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FURTHER INFORMATION

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PowerPoint slides

Glossary

Linkage disequilibrium

The nonrandom association of alleles at different loci, for example, owing to close physical proximity within a genomic region.

Gene conversion

The process by which one allele is converted to another by mismatch repair mechanisms.

Heterozygote advantage

The increased relative fitness of an organism conferred by having two different forms of a genetic variant, as opposed to having two identical copies of either of the two forms.

Frequency-dependent selection

An evolutionary process whereby fitness of a given phenotype depends on its frequency relative to other phenotypes in a study population. Positive selection will occur if the fitness of the phenotype increases as its frequency increases, whereas negative selection will occur if the fitness decreases as the frequency of the phenotype increases.

HLA restriction

A property of T cells whereby a given T cell receptor will recognize and respond to an antigen only when it is presented by a particular HLA molecule.

Neoantigens

Non-germline-encoded (and thus non-inherited) antigens that may arise because of somatic mutation (as in cancer) or other processes such as post-translational modification and splicing together of peptides.

Pancreatic islets

Clusters of different cell types found throughout the pancreas that include the insulin-producing β-cells, which are a main target of the autoimmune response occurring in patients with type 1 diabetes.

Allomorphs

Different MHC protein forms encoded by different alleles.

Unfolded protein response

A cellular stress response triggered because of the accumulation of unfolded or misfolded proteins within the endoplasmic reticulum.

Epitope spreading

Describes how a self-directed immune response induced by a single peptide (or epitope) could spread to include other peptides (or epitopes), not only on the same autoantigen (intramolecular spreading) but also on other self molecules in close vicinity to the target cell (intermolecular spreading).

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Dendrou, C., Petersen, J., Rossjohn, J. et al. HLA variation and disease. Nat Rev Immunol 18, 325–339 (2018). https://doi.org/10.1038/nri.2017.143

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