Self-Antigens Targeted by Regulatory T Cells in Type 1 Diabetes

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2022 Mar 25

PMID 35328581

Authors

Angela M Mitchell

Aaron W Michels

Affiliations

Soon will be listed here.

Abstract

While progress has been made toward understanding mechanisms that lead to the development of autoimmunity, there is less knowledge regarding protective mechanisms from developing such diseases. For example, in type 1 diabetes (T1D), the immune-mediated form of diabetes, the role of pathogenic T cells in the destruction of pancreatic islets is well characterized, but immune-mediated mechanisms that contribute to T1D protection have not been fully elucidated. One potential protective mechanism includes the suppression of immune responses by regulatory CD4 T cells (Tregs) that recognize self-peptides from islets presented by human leukocyte antigen (HLA) class II molecules. In this review, we summarize what is known about the antigenic self-peptides recognized by Tregs in the context of T1D.

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References

Haseda F, Imagawa A, Murase-Mishiba Y, Terasaki J, Hanafusa T . CD4⁺ CD45RA⁻ FoxP3high activated regulatory T cells are functionally impaired and related to residual insulin-secreting capacity in patients with type 1 diabetes. Clin Exp Immunol. 2013; 173(2):207-16. PMC: 3722921. DOI: 10.1111/cei.12116. View

Putnam A, Brusko T, Lee M, Liu W, Szot G, Ghosh T . Expansion of human regulatory T-cells from patients with type 1 diabetes. Diabetes. 2008; 58(3):652-62. PMC: 2646064. DOI: 10.2337/db08-1168. View

Wicker L, Miller B, FISCHER P, Pressey A, Peterson L . Genetic control of diabetes and insulitis in the nonobese diabetic mouse. Pedigree analysis of a diabetic H-2nod/b heterozygote. J Immunol. 1989; 142(3):781-4. View

Herold K, Bundy B, Long S, Bluestone J, DiMeglio L, Dufort M . An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes. N Engl J Med. 2019; 381(7):603-613. PMC: 6776880. DOI: 10.1056/NEJMoa1902226. View

Yang J, Danke N, Berger D, Reichstetter S, Reijonen H, Greenbaum C . Islet-specific glucose-6-phosphatase catalytic subunit-related protein-reactive CD4+ T cells in human subjects. J Immunol. 2006; 176(5):2781-9. DOI: 10.4049/jimmunol.176.5.2781. View

Kaestner K, Powers A, Naji A, Atkinson M . NIH Initiative to Improve Understanding of the Pancreas, Islet, and Autoimmunity in Type 1 Diabetes: The Human Pancreas Analysis Program (HPAP). Diabetes. 2019; 68(7):1394-1402. PMC: 6609987. DOI: 10.2337/db19-0058. View

Ziegler A, Rewers M, Simell O, Simell T, Lempainen J, Steck A . Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA. 2013; 309(23):2473-9. PMC: 4878912. DOI: 10.1001/jama.2013.6285. View

Hu X, Deutsch A, Lenz T, Onengut-Gumuscu S, Han B, Chen W . Additive and interaction effects at three amino acid positions in HLA-DQ and HLA-DR molecules drive type 1 diabetes risk. Nat Genet. 2015; 47(8):898-905. PMC: 4930791. DOI: 10.1038/ng.3353. View

Arif S, Tree T, Astill T, Tremble J, Bishop A, Dayan C . Autoreactive T cell responses show proinflammatory polarization in diabetes but a regulatory phenotype in health. J Clin Invest. 2004; 113(3):451-63. PMC: 324541. DOI: 10.1172/JCI19585. View

10.

Arribas-Layton D, Guyer P, Delong T, Dang M, Chow I, Speake C . Hybrid Insulin Peptides Are Recognized by Human T Cells in the Context of DRB1*04:01. Diabetes. 2020; 69(7):1492-1502. PMC: 7306133. DOI: 10.2337/db19-0620. View

11.

Scherm M, Serr I, Zahm A, Schug J, Bellusci S, Manfredini R . miRNA142-3p targets Tet2 and impairs Treg differentiation and stability in models of type 1 diabetes. Nat Commun. 2019; 10(1):5697. PMC: 6910913. DOI: 10.1038/s41467-019-13587-3. View

12.

Haller M, Gitelman S, Gottlieb P, Michels A, Rosenthal S, Shuster J . Anti-thymocyte globulin/G-CSF treatment preserves β cell function in patients with established type 1 diabetes. J Clin Invest. 2014; 125(1):448-55. PMC: 4382237. DOI: 10.1172/JCI78492. View

13.

Serr I, Furst R, Ott V, Scherm M, Nikolaev A, Gokmen F . miRNA92a targets KLF2 and the phosphatase PTEN signaling to promote human T follicular helper precursors in T1D islet autoimmunity. Proc Natl Acad Sci U S A. 2016; 113(43):E6659-E6668. PMC: 5087025. DOI: 10.1073/pnas.1606646113. View

14.

Atkinson M, Eisenbarth G, Michels A . Type 1 diabetes. Lancet. 2013; 383(9911):69-82. PMC: 4380133. DOI: 10.1016/S0140-6736(13)60591-7. View

15.

Hinman R, Cambier J . Role of B lymphocytes in the pathogenesis of type 1 diabetes. Curr Diab Rep. 2014; 14(11):543. DOI: 10.1007/s11892-014-0543-8. View

16.

Barrett J, Clayton D, Concannon P, Akolkar B, Cooper J, Erlich H . Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet. 2009; 41(6):703-7. PMC: 2889014. DOI: 10.1038/ng.381. View

17.

Delong T, Wiles T, Baker R, Bradley B, Barbour G, Reisdorph R . Pathogenic CD4 T cells in type 1 diabetes recognize epitopes formed by peptide fusion. Science. 2016; 351(6274):711-4. PMC: 4884646. DOI: 10.1126/science.aad2791. View

18.

Sockolosky J, Trotta E, Parisi G, Picton L, Su L, Le A . Selective targeting of engineered T cells using orthogonal IL-2 cytokine-receptor complexes. Science. 2018; 359(6379):1037-1042. PMC: 5947856. DOI: 10.1126/science.aar3246. View

19.

Pugliese A . Autoreactive T cells in type 1 diabetes. J Clin Invest. 2017; 127(8):2881-2891. PMC: 5531393. DOI: 10.1172/JCI94549. View

20.

Long S, Rieck M, Sanda S, Bollyky J, Samuels P, Goland R . Rapamycin/IL-2 combination therapy in patients with type 1 diabetes augments Tregs yet transiently impairs β-cell function. Diabetes. 2012; 61(9):2340-8. PMC: 3425404. DOI: 10.2337/db12-0049. View