Responses Against Islet Antigens in NOD Mice Are Prevented by Tolerance to Proinsulin but Not IGRP

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2006 Dec 5

PMID 17143333

Citations 119

Authors

Balasubramanian Krishnamurthy

Nadine L Dudek

Mark D McKenzie

Anthony W Purcell

Andrew G Brooks

Shane Gellert

Peter G Colman

Leonard C Harrison

Andrew M Lew

Helen E Thomas

Thomas W H Kay

Affiliations

Soon will be listed here.

Abstract

Type 1 diabetes (T1D) is characterized by immune responses against several autoantigens expressed in pancreatic beta cells. T cells specific for proinsulin and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) can induce T1D in NOD mice. However, whether immune responses to multiple autoantigens are caused by spreading from one to another or whether they develop independently of each other is unknown. As cytotoxic T cells specific for IGRP were not detected in transgenic NOD mice tolerant to proinsulin, we determined that immune responses against proinsulin are necessary for IGRP-specific T cells to develop. On the other hand, transgenic overexpression of IGRP resulted in loss of intra-islet IGRP-specific T cells but did not protect NOD mice from insulitis or T1D, providing direct evidence that the response against IGRP is downstream of the response to proinsulin. Our results suggest that pathogenic proinsulin-specific immunity in NOD mice subsequently spreads to other antigens such as IGRP.

Citing Articles

Insulin-degrading enzyme regulates insulin-directed cellular autoimmunity in murine type 1 diabetes.

Bessard M, Moser A, Waeckel-Enee E, Lindo V, Gdoura A, You S Front Immunol. 2024; 15:1474453.

PMID: 39600694 PMC: 11588737. DOI: 10.3389/fimmu.2024.1474453.

Multifaceted Roles of Vitamin D for Diabetes: From Immunomodulatory Functions to Metabolic Regulations.

Park C, Shin S, Han S Nutrients. 2024; 16(18).

PMID: 39339785 PMC: 11435169. DOI: 10.3390/nu16183185.

Antigen-specific T cell responses in autoimmune diabetes.

Dwyer A, Shaheen Z, Fife B Front Immunol. 2024; 15:1440045.

PMID: 39211046 PMC: 11358097. DOI: 10.3389/fimmu.2024.1440045.

Extraislet expression of islet antigen boosts T cell exhaustion to partially prevent autoimmune diabetes.

Selck C, Jhala G, De George D, Kwong C, Christensen M, Pappas E Proc Natl Acad Sci U S A. 2024; 121(6):e2315419121.

PMID: 38285952 PMC: 10861925. DOI: 10.1073/pnas.2315419121.

The beta cell-immune cell interface in type 1 diabetes (T1D).

James E, Joglekar A, Linnemann A, Russ H, Kent S Mol Metab. 2023; 78:101809.

PMID: 37734713 PMC: 10622886. DOI: 10.1016/j.molmet.2023.101809.

References

Trudeau J, Kelly-Smith C, Verchere C, Elliott J, Dutz J, Finegood D . Prediction of spontaneous autoimmune diabetes in NOD mice by quantification of autoreactive T cells in peripheral blood. J Clin Invest. 2003; 111(2):217-23. PMC: 151866. DOI: 10.1172/JCI16409. View

Son Y, Egawa S, Tatsumi T, Redlinger Jr R, Kalinski P, Kanto T . A novel bulk-culture method for generating mature dendritic cells from mouse bone marrow cells. J Immunol Methods. 2002; 262(1-2):145-57. DOI: 10.1016/s0022-1759(02)00013-3. View

Steptoe R, Ritchie J, Harrison L . Transfer of hematopoietic stem cells encoding autoantigen prevents autoimmune diabetes. J Clin Invest. 2003; 111(9):1357-63. PMC: 154439. DOI: 10.1172/JCI15995. View

Jaeckel E, Klein L, Martin-Orozco N, von Boehmer H . Normal incidence of diabetes in NOD mice tolerant to glutamic acid decarboxylase. J Exp Med. 2003; 197(12):1635-44. PMC: 2193961. DOI: 10.1084/jem.20030215. View

Lieberman S, Evans A, Han B, Takaki T, Vinnitskaya Y, Caldwell J . Identification of the beta cell antigen targeted by a prevalent population of pathogenic CD8+ T cells in autoimmune diabetes. Proc Natl Acad Sci U S A. 2003; 100(14):8384-8. PMC: 166238. DOI: 10.1073/pnas.0932778100. View

Heath W, Belz G, Behrens G, Smith C, Forehan S, Parish I . Cross-presentation, dendritic cell subsets, and the generation of immunity to cellular antigens. Immunol Rev. 2004; 199:9-26. DOI: 10.1111/j.0105-2896.2004.00142.x. View

Jaeckel E, Lipes M, von Boehmer H . Recessive tolerance to preproinsulin 2 reduces but does not abolish type 1 diabetes. Nat Immunol. 2004; 5(10):1028-35. DOI: 10.1038/ni1120. View

Vremec D, Zorbas M, Scollay R, Saunders D, Ardavin C, Wu L . The surface phenotype of dendritic cells purified from mouse thymus and spleen: investigation of the CD8 expression by a subpopulation of dendritic cells. J Exp Med. 1992; 176(1):47-58. PMC: 2119290. DOI: 10.1084/jem.176.1.47. View

Wong F, Visintin I, Wen L, Flavell R, Janeway Jr C . CD8 T cell clones from young nonobese diabetic (NOD) islets can transfer rapid onset of diabetes in NOD mice in the absence of CD4 cells. J Exp Med. 1996; 183(1):67-76. PMC: 2192404. DOI: 10.1084/jem.183.1.67. View

10.

Tisch R, McDevitt H . Insulin-dependent diabetes mellitus. Cell. 1996; 85(3):291-7. DOI: 10.1016/s0092-8674(00)81106-x. View

11.

Verdaguer J, Yoon J, Anderson B, Averill N, Utsugi T, Park B . Acceleration of spontaneous diabetes in TCR-beta-transgenic nonobese diabetic mice by beta-cell cytotoxic CD8+ T cells expressing identical endogenous TCR-alpha chains. J Immunol. 1996; 157(10):4726-35. View

12.

French M, Allison J, Cram D, Thomas H, Silva A, Georgiou H . Transgenic expression of mouse proinsulin II prevents diabetes in nonobese diabetic mice. Diabetes. 1997; 46(1):34-9. DOI: 10.2337/diab.46.1.34. View

13.

Williams A, Bingley P, Bonifacio E, Palmer J, Gale E . A novel micro-assay for insulin autoantibodies. J Autoimmun. 1997; 10(5):473-8. DOI: 10.1006/jaut.1997.0154. View

14.

Verdaguer J, Schmidt D, Amrani A, Anderson B, Averill N, Santamaria P . Spontaneous autoimmune diabetes in monoclonal T cell nonobese diabetic mice. J Exp Med. 1997; 186(10):1663-76. PMC: 2199139. DOI: 10.1084/jem.186.10.1663. View

15.

Thomas H, Parker J, Schreiber R, Kay T . IFN-gamma action on pancreatic beta cells causes class I MHC upregulation but not diabetes. J Clin Invest. 1998; 102(6):1249-57. PMC: 509108. DOI: 10.1172/JCI2899. View

16.

DiLorenzo T, Graser R, Ono T, Christianson G, Chapman H, Roopenian D . Major histocompatibility complex class I-restricted T cells are required for all but the end stages of diabetes development in nonobese diabetic mice and use a prevalent T cell receptor alpha chain gene rearrangement. Proc Natl Acad Sci U S A. 1998; 95(21):12538-43. PMC: 22866. DOI: 10.1073/pnas.95.21.12538. View

17.

Ziegler A, Hummel M, Schenker M, Bonifacio E . Autoantibody appearance and risk for development of childhood diabetes in offspring of parents with type 1 diabetes: the 2-year analysis of the German BABYDIAB Study. Diabetes. 1999; 48(3):460-8. DOI: 10.2337/diabetes.48.3.460. View

18.

Wong F, Karttunen J, Dumont C, Wen L, Visintin I, Pilip I . Identification of an MHC class I-restricted autoantigen in type 1 diabetes by screening an organ-specific cDNA library. Nat Med. 1999; 5(9):1026-31. DOI: 10.1038/12465. View

19.

McMahon E, Bailey S, Castenada C, Waldner H, Miller S . Epitope spreading initiates in the CNS in two mouse models of multiple sclerosis. Nat Med. 2005; 11(3):335-9. DOI: 10.1038/nm1202. View

20.

Mukherjee R, Wagar D, Stephens T, Lee-Chan E, Singh B . Identification of CD4+ T cell-specific epitopes of islet-specific glucose-6-phosphatase catalytic subunit-related protein: a novel beta cell autoantigen in type 1 diabetes. J Immunol. 2005; 174(9):5306-15. DOI: 10.4049/jimmunol.174.9.5306. View