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Cited by 63Diabetes and associated disordersT-cell and B-cell Immunologyvaccines and immunoinformatics approaches

Antigen Presentation in the Autoimmune Diabetes of the NOD Mouse

Open access
Unanue, Emil R.·2014·Annual Review of Immunology
DOI 10.1146/annurev-immunol-032712-095941
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Abstract

This paper reviews the presentation of peptides by major histocompatibility complex (MHC) class II molecules in the autoimmune diabetes of the nonobese diabetic (NOD) mouse. Islets of Langerhans contain antigen-presenting cells that capture the proteins and peptides of the beta cells' secretory granules. Peptides bound to I-A g7 , the unique MHC class II molecule of NOD mice, are presented in islets and in pancreatic lymph nodes. The various beta cell–derived peptides interact with selected CD4 T cells to cause inflammation and beta cell demise. Many autoreactive T cells are found in NOD mice, but not all have a major role in the initiation of the autoimmune process. I emphasize here the evidence pointing to insulin autoreactivity as a seminal component in the diabetogenic process.

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  • The non-obese diabetic (NOD) mouse model is a clinically relevant model of T1D and shares many features with the human disease, including spontaneous CD4 and CD8 T cell responses to many of the same β-cell antigens.

    “The non-obese diabetic (NOD) mouse model is a clinically relevant model of T1D6,7 and shares many features with the human disease, including spontaneous CD4 and CD8 T cell responses to many of the same β-cell antigens6–9.”

    From An autoimmune stem-like CD8 T cell population drives type 1 diabetes (2022) · cites this paper as [7]

    The Introduction and Conclusions describe NOD mice as a spontaneous model of T1D with important similarities to human disease. The Diabetogenic CD4 T Cells section reports broad β-cell autoreactivity and identifies both CD4 and CD8 T cells in NOD mice; Human Studies also reports insulin-reactive T cells in people with T1D. But the paper does not establish spontaneous CD4 and CD8 responses to many of the same β-cell antigens in both species, and the Conclusions explicitly leave the human counterpart of a described NOD CD4 response as an open question. (LLM, conf=0.86)

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Cites

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Research works printed but not linked: 19

  1. Acha-Orbea H, McDevitt HO. 1987. The first external domain of the nonobese diabetic mouse class II I-A β chain is unique. Proc. Natl. Acad. Sci. USA 84:2435-39
  2. Lee KH, Wucherpfenning KW, Wiley DC. 2001. Structure of a human insulin peptide-HLA-DQ8 complex and susceptibility to type 1 diabetes. Nat. Immunol. 2:501-7
  3. Calderon B, Suri A, Miller M, Unanue ER. 2008. Dendritic cells in islets of Langerhans constitutively present β cell-derived peptides bound to their class II MHC molecules. Proc. Natl. Acad. Sci. USA 105:6121-26
  4. Calderon B, Carrero JA, Miller MJ, Unanue ER. 2011. Cellular and molecular events in the localization of diabetogenic T cells to islets of Langerhans. Proc. Natl. Acad. Sci. USA 108:1561-66
  5. Calderon B, Carrero JA, Miller MJ, Unanue ER. 2011. Entry of diabetogenic T cells into islets induces changes that lead to amplification of the cellular response. Proc. Natl. Acad. Sci. USA 108:567-72
  6. Haskins K, Portas M, Bergman B, Lafferty K, Bradley B. 1989. Pancreatic islet-specific T-cell clones from nonobese diabetic mice. Proc. Natl. Acad. Sci. USA 86:8000-4
  7. Renold AE, Soeldner S, Steinke J. 1964. Immunologic studies with homologous and heterologous pan- creatic insulin in the cow. In Aetiology of Diabetes Mellitus and Its Complications, ed. MP Cameron, M O'Connor, pp. 122-39. Chichester, UK: Wiley
  8. Bell GI, Karam JH, Rutter WJ. 1981. Polymorphic DNA region adjacent to the 5 end of the human insulin gene. Proc. Natl. Acad. Sci. USA 78:5759-63
  9. Yu L, Robles DT, Abiru N, Kaur P, Rewers M, et al. 2000. Early expression of antiinsulin autoantibodies of humans and the NOD mouse: evidence for early determination of subsequent diabetes. Proc. Natl. Acad. Sci. USA 97:1701-6
  10. Moriyama H, Abiru N, Paronen J, Sikora K, Liu E, et al. 2003. Evidence for a primary islet autoantigen (preproinsulin1) for insulitis and diabetes in the nonobese diabetic mouse. Proc. Natl. Acad. Sci. USA 100:10376-81
  11. Pinto S, Michel C, Schmidt-Glenewinkel H, Harder N, Rohr K, et al. 2013. Overlapping gene coex- pression patterns in human medullary thymic epithelial cells generate self-antigen diversity. Proc. Natl. Acad. Sci. USA 110:E3497-505
  12. Crawford M, Daniel D, Wegmann D, Yang H, Gill RG. 1997. Autoimmune islet damage mediated by insulin-specific T cells. Transplant. Proc. 29:758-59 118.
  13. Crawford F, Stadinski B, Jin N, Michels A, Nakayama M, et al. 2011. Specificity and detection of insulin- reactive CD4 + T cells in type 1 diabetes in the nonobese diabetic (NOD) mouse. Proc. Natl. Acad. Sci. USA 108:16729-34 122.
  14. Stadinski BD, Zhang L, Crawford F, Marrack P, Eisenbarth GS, Kappler JW. 2010. Diabetogenic T cells recognize insulin bound to IA g7 in an unexpected, weakly binding register. Proc. Natl. Acad. Sci. USA 107:10978-83 125.
  15. Wong FS, Moustakas AK, Wen L, Papadopoulos GK, Janeway CA Jr. 2002. Analysis of structure and function relationships of an autoantigenic peptide of insulin bound to H-2K d that stimulates CD8 T cells in insulin-dependent diabetes mellitus. Proc. Natl. Acad. Sci. USA 99:5551-56 127.
  16. Chao CC, Sytwu HK, Chen EL, Toma J, McDevitt HO. 1999. The role of MHC class II molecules in susceptibility to type I diabetes: identification of peptide epitopes and characterization of the T cell repertoire. Proc. Natl. Acad. Sci. USA 96:9299-304 128.
  17. Suri A, Walters JJ, Kanagawa O, Gross ML, Unanue ER. 2003. Specificity of peptide selection by APCs homozygous or heterozygous for expression of class II MHC molecules-the lack of competition. Proc. Natl. Acad. Sci. USA 100:5330-35 135.
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Authors
Unanue, E. R.
Affiliations
Washington University in St. Louis (US)
Corresponding author
Unanue, Emil R.
ORCID
Unanue, Emil R.
Venue
Annual Review of Immunology
Publisher
Annual Reviews
Published
2014-03-21
Volume
32
Issue
1
Pages
579-608
ISSN
  • 0732-0582 (ISSN-L)
  • 1545-3278
DOI
10.1146/annurev-immunol-032712-095941
OpenAlex
W2136729344
Cited by
63
References
6
Citations by year
2026: 1 · 2025: 7 · 2024: 6 · 2023: 4 · 2022: 1 · 2021: 4 · 2020: 5 · 2019: 3 · 2018: 6 · 2017: 5 · 2016: 14 · 2015: 5 · 2014: 2
FWCI
1.15
Type
journal article
Language
en
Open access
Locations
  • Annual Review of Immunology (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK058177)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
Keywords
antigen presentation, autoimmune diabetes, NOD mice, MHC class II, I-Ag7, pancreatic islets, CD4+ T cells, autoreactive T cells, beta cell destruction, pancreatic lymph nodes, type 1 diabetes
MeSH terms
Animals, Antigen-Presenting Cells, Histocompatibility Antigens Class II, Autoantigens, Diabetes Mellitus, Type 1, Disease Models, Animal, Humans, Insulin, Islets of Langerhans, Lymphocyte Activation, Peptides, T-Lymphocyte Subsets, Mice, Inbred NOD, Antigen Presentation, Epitopes, T-Lymphocyte, T-Cell Antigen Receptor Specificity, Mice

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