Noncontiguous T cell epitopes in autoimmune diabetes: From mice to men and back again
2021; Elsevier BV; Volume: 297; Issue: 1 Linguagem: Inglês
10.1016/j.jbc.2021.100827
ISSN1083-351X
AutoresNitin Amdare, Anthony W. Purcell, Teresa P. DiLorenzo,
Tópico(s)Pancreatic function and diabetes
ResumoType 1 diabetes (T1D) is a T cell–mediated autoimmune disease that affects the insulin-producing beta cells of the pancreatic islets. The nonobese diabetic mouse is a widely studied spontaneous model of the disease that has contributed greatly to our understanding of T1D pathogenesis. This is especially true in the case of antigen discovery. Upon review of existing knowledge concerning the antigens and peptide epitopes that are recognized by T cells in this model, good concordance is observed between mouse and human antigens. A fascinating recent illustration of the contribution of the nonobese diabetic mouse in the area of epitope identification is the discovery of noncontiguous CD4+ T cell epitopes. This novel epitope class is characterized by the linkage of an insulin-derived peptide to, most commonly, a fragment of a natural cleavage product of another beta cell secretory granule constituent. These so-called hybrid insulin peptides are also recognized by T cells in patients with T1D, although the precise mechanism for their generation has yet to be defined and is the subject of active investigation. Although evidence from the tumor immunology arena documented the existence of noncontiguous CD8+ T cell epitopes, generated by proteasome-mediated peptide splicing involving transpeptidation, such CD8+ T cell epitopes were thought to be a rare immunological curiosity. However, recent advances in bioinformatics and mass spectrometry have challenged this view. These developments, coupled with the discovery of hybrid insulin peptides, have spurred a search for noncontiguous CD8+ T cell epitopes in T1D, an exciting frontier area still in its infancy. Type 1 diabetes (T1D) is a T cell–mediated autoimmune disease that affects the insulin-producing beta cells of the pancreatic islets. The nonobese diabetic mouse is a widely studied spontaneous model of the disease that has contributed greatly to our understanding of T1D pathogenesis. This is especially true in the case of antigen discovery. Upon review of existing knowledge concerning the antigens and peptide epitopes that are recognized by T cells in this model, good concordance is observed between mouse and human antigens. A fascinating recent illustration of the contribution of the nonobese diabetic mouse in the area of epitope identification is the discovery of noncontiguous CD4+ T cell epitopes. This novel epitope class is characterized by the linkage of an insulin-derived peptide to, most commonly, a fragment of a natural cleavage product of another beta cell secretory granule constituent. These so-called hybrid insulin peptides are also recognized by T cells in patients with T1D, although the precise mechanism for their generation has yet to be defined and is the subject of active investigation. Although evidence from the tumor immunology arena documented the existence of noncontiguous CD8+ T cell epitopes, generated by proteasome-mediated peptide splicing involving transpeptidation, such CD8+ T cell epitopes were thought to be a rare immunological curiosity. However, recent advances in bioinformatics and mass spectrometry have challenged this view. These developments, coupled with the discovery of hybrid insulin peptides, have spurred a search for noncontiguous CD8+ T cell epitopes in T1D, an exciting frontier area still in its infancy. Beta cells in the pancreatic islets of Langerhans synthesize and secrete insulin, a hormone required for glucose utilization and homeostasis. In autoimmune diabetes, also known as type 1 diabetes (T1D), beta cells are destroyed by T cells that have been activated by islet-derived peptides bound to major histocompatibility complex (MHC) molecules, either displayed by the beta cells themselves or by professional antigen-presenting cells (APCs) (1Pugliese A. Autoreactive T cells in type 1 diabetes.J. Clin. Invest. 2017; 127: 2881-2891Crossref PubMed Scopus (112) Google Scholar). Consistent with the presence of CD4+ and CD8+ T cells specific for beta cell–derived peptides in the islets of donors with T1D (2Babon J.A. DeNicola M.E. Blodgett D.M. Crevecoeur I. Buttrick T.S. Maehr R. Bottino R. Naji A. Kaddis J. Elyaman W. James E.A. Haliyur R. Brissova M. Overbergh L. Mathieu C. et al.Analysis of self-antigen specificity of islet-infiltrating T cells from human donors with type 1 diabetes.Nat. Med. 2016; 22: 1482-1487Crossref PubMed Google Scholar), both T cell subsets are believed to participate in beta cell elimination. Based on studies in rodent models, T cells likely employ a variety of mechanisms to achieve this end, including Fas-mediated apoptosis and the release of effector molecules such as perforin, granzyme, and the cytokines interferon-γ and tumor necrosis factor-α (3Dudek N.L. Thomas H.E. Mariana L. Sutherland R.M. Allison J. Estella E. Angstetra E. Trapani J.A. Santamaria P. Lew A.M. Kay T.W. Cytotoxic T-cells from T-cell receptor transgenic NOD8.3 mice destroy β-cells via the perforin and Fas pathways.Diabetes. 2006; 55: 2412-2418Crossref PubMed Scopus (0) Google Scholar, 4McKenzie M.D. Dudek N.L. Mariana L. Chong M.M. Trapani J.A. Kay T.W. Thomas H.E. Perforin and Fas induced by IFNγ and TNFα mediate beta cell death by OT-I CTL.Int. Immunol. 2006; 18: 837-846Crossref PubMed Scopus (0) Google Scholar). In the absence of a sufficient beta cell mass, exogenous insulin becomes necessary for survival. T1D is a complex disease with both genetic and environmental components (5Katsarou A. Gudbjornsdottir S. Rawshani A. Dabelea D. Bonifacio E. Anderson B.J. Jacobsen L.M. Schatz D.A. Lernmark A. Type 1 diabetes mellitus.Nat. Rev. Dis. Primers. 2017; 3: 17016Crossref PubMed Scopus (305) Google Scholar). Polymorphisms in dozens of genes contribute to disease susceptibility or resistance (6Redondo M.J. Steck A.K. Pugliese A. Genetics of type 1 diabetes.Pediatr. Diabetes. 2018; 19: 346-353Crossref PubMed Scopus (56) Google Scholar). The majority are expressed by cells of the immune system or by the pancreatic beta cells themselves, reflecting a complicated interplay between autoreactive T cells and beta cells. Environmental triggers (e.g., viral infection or dietary components) that initiate an often protracted, and initially asymptomatic, autoimmune process in genetically susceptible individuals are assumed, but remain ill-defined (7Dedrick S. Sundaresh B. Huang Q. Brady C. Yoo T. Cronin C. Rudnicki C. Flood M. Momeni B. Ludvigsson J. Altindis E. The role of gut microbiota and environmental factors in type 1 diabetes pathogenesis.Front. Endocrinol. (Lausanne). 2020; 11: 78Crossref PubMed Scopus (11) Google Scholar). Adding to the complexity is the finding of serum autoantibodies to beta cell proteins, often years before the onset of clinical symptoms (8Ziegler A.G. Rewers M. Simell O. Simell T. Lempainen J. Steck A. Winkler C. Ilonen J. Veijola R. Knip M. Bonifacio E. Eisenbarth G.S. Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children.J. Am. Med. Assoc. 2013; 309: 2473-2479Crossref PubMed Scopus (563) Google Scholar). Although autoantibodies are of great utility in predicting individuals who will develop T1D, a pathogenic role for the autoantibodies has not been established, and the disease is viewed as being mediated by T cells rather than by antibodies. Given the essential role of T cell epitopes in the pathogenesis of T1D, it is unsurprising that multiple benefits have been derived from their identification, and others can be readily envisioned. Knowledge regarding the T cell epitopes in T1D has provided critical insights into the mechanistic basis of the disease process. For example, it was once satisfying to believe that patients with T1D would harbor T cells specific for beta cell antigens, whereas healthy controls would be devoid of them, having been successfully purged of autoreactive T cells by the central tolerance mechanism of thymic negative selection. However, the identification of T cell epitopes in T1D now allows T cells specific for beta cell antigens to be quantitatively and functionally assessed (albeit thus far for research purposes only), leading to the important realization that CD4+ and CD8+ T cells reactive to beta cell peptides are present in both health and disease (9Arif S. Tree T.I. Astill T.P. Tremble J.M. Bishop A.J. Dayan C.M. Roep B.O. Peakman M. Autoreactive T cell responses show proinflammatory polarization in diabetes but a regulatory phenotype in health.J. Clin. Invest. 2004; 113: 451-463Crossref PubMed Google Scholar, 10Culina S. Lalanne A.I. Afonso G. Cerosaletti K. Pinto S. Sebastiani G. Kuranda K. Nigi L. Eugster A. Osterbye T. Maugein A. McLaren J.E. Ladell K. Larger E. Beressi J.P. et al.Islet-reactive CD8+ T cell frequencies in the pancreas, but not in blood, distinguish type 1 diabetic patients from healthy donors.Sci. Immunol. 2018; 3eaao4013Crossref PubMed Google Scholar). Yet, differences in T cell numbers and/or function are often noted when the two states are compared (11James E.A. Mallone R. Kent S.C. DiLorenzo T.P. T-cell epitopes and neo-epitopes in type 1 diabetes: A comprehensive update and reappraisal.Diabetes. 2020; 69: 1311-1335Crossref PubMed Scopus (12) Google Scholar), suggesting the potential utility of antigen-specific T cell assays for immune monitoring, e.g., in disease prevention and reversal trials, or as diagnostic tools. The promise and feasibility of T cell–based assays in a clinical setting is exemplified by the interferon-γ release assays that are currently used in the diagnosis of latent Mycobacterium tuberculosis (Mtb) infection (12Whitworth H.S. Scott M. Connell D.W. Donges B. Lalvani A. IGRAs--the gateway to T cell based TB diagnosis.Methods. 2013; 61: 52-62Crossref PubMed Scopus (0) Google Scholar). In these assays, peripheral blood cells are exposed to peptides derived from known Mtb antigens, and Mtb-specific T cells are detected by the interferon-γ they release in response to recognition of their cognate epitopes. Finally, in addition to representing important components of a future clinical assay to detect beta cell–specific T cells, T cell epitopes are also being explored in clinical trials as preventive or therapeutic agents for T1D (13Smith E.L. Peakman M. Peptide immunotherapy for type 1 diabetes-clinical advances.Front. Immunol. 2018; 9: 392Crossref PubMed Scopus (4) Google Scholar). With the above goals and opportunities in mind, discovery of T cell epitopes in T1D continues to be an active area of investigation, and the known peptides recognized by T1D-associated T cells in humans have recently been compiled and evaluated (11James E.A. Mallone R. Kent S.C. DiLorenzo T.P. T-cell epitopes and neo-epitopes in type 1 diabetes: A comprehensive update and reappraisal.Diabetes. 2020; 69: 1311-1335Crossref PubMed Scopus (12) Google Scholar). Although the majority of the epitopes identified to date are conventional peptides, T1D-associated T cell epitopes may also be posttranslationally modified or otherwise unconventional (11James E.A. Mallone R. Kent S.C. DiLorenzo T.P. T-cell epitopes and neo-epitopes in type 1 diabetes: A comprehensive update and reappraisal.Diabetes. 2020; 69: 1311-1335Crossref PubMed Scopus (12) Google Scholar) (Fig. 1). In view of the known clinical importance of an immune response to posttranslationally modified peptides in rheumatoid arthritis (14Darrah E. Andrade F. Rheumatoid arthritis and citrullination.Curr. Opin. Rheumatol. 2018; 30: 72-78Crossref PubMed Scopus (57) Google Scholar) and celiac disease (15Sollid L.M. The roles of MHC class II genes and post-translational modification in celiac disease.Immunogenetics. 2017; 69: 605-616Crossref PubMed Scopus (46) Google Scholar), there is currently considerable interest in unconventional epitopes in T1D as well. The collection of biochemical processes that create unconventional T cell epitopes in T1D (Fig. 1) includes disulfide bond formation (16Mannering S.I. Harrison L.C. Williamson N.A. Morris J.S. Thearle D.J. Jensen K.P. Kay T.W. Rossjohn J. Falk B.A. Nepom G.T. Purcell A.W. The insulin A-chain epitope recognized by human T cells is posttranslationally modified.J. Exp. Med. 2005; 202: 1191-1197Crossref PubMed Scopus (160) Google Scholar), deamidation (2Babon J.A. DeNicola M.E. Blodgett D.M. Crevecoeur I. Buttrick T.S. Maehr R. Bottino R. Naji A. Kaddis J. Elyaman W. James E.A. Haliyur R. Brissova M. Overbergh L. Mathieu C. et al.Analysis of self-antigen specificity of islet-infiltrating T cells from human donors with type 1 diabetes.Nat. Med. 2016; 22: 1482-1487Crossref PubMed Google Scholar, 17Marre M.L. McGinty J.W. Chow I.T. DeNicola M.E. Beck N.W. Kent S.C. Powers A.C. Bottino R. Harlan D.M. Greenbaum C.J. Kwok W.W. Piganelli J.D. James E.A. 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Lowe C. et al.Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease.Nature. 2003; 423: 506-511Crossref PubMed Scopus (1744) Google Scholar) and diminished function of CD4+CD25+ regulatory T cells, essential for peripheral tolerance, due to gene variants affecting interleukin 2 signaling (44Lowe C.E. Cooper J.D. Brusko T. Walker N.M. Smyth D.J. Bailey R. Bourget K. Plagnol V. Field S. Atkinson M. Clayton D.G. Wicker L.S. Todd J.A. Large-scale genetic fine mapping and genotype-phenotype associations implicate polymorphism in the IL2RA region in type 1 diabetes.Nat. Genet. 2007; 39: 1074-1082Crossref PubMed Scopus (291) Google Scholar, 45Vella A. Cooper J.D. Lowe C.E. Walker N. Nutland S. Widmer B. Jones R. Ring S.M. McArdle W. Pembrey M.E. Strachan D.P. Dunger D.B. Twells R.C. Clayton D.G. Todd J.A. Localization of a type 1 diabetes locus in the IL2RA/CD25 region by use of tag single-nucleotide polymorphisms.Am. J. Hum. 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