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Unique autoreactive T cells recognize insulin peptides generated within the islets of Langerhans in autoimmune diabetes

Nature Immunology volume 11, pages 350–354 (2010)Cite this article

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Abstract

In addition to the genetic framework, there are two other critical requirements for the development of tissue-specific autoimmune disease. First, autoreactive T cells need to escape thymic negative selection. Second, they need to find suitable conditions for autoantigen presentation and activation in the target tissue. We show here that these two conditions are fulfilled in diabetic mice of the nonobese diabetic (NOD) strain. A set of autoreactive CD4+ T cells specific for an insulin peptide, with the noteworthy feature of not recognizing the insulin protein when processed by antigen-presenting cells (APCs), escaped thymic control, participated in diabetes and caused disease. Moreover, APCs in close contact with beta cells in the islets of Langerhans bore vesicles with the antigenic insulin peptides and activated peptide-specific T cells. Our findings may be relevant for other cases of endocrine autoimmunity.

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Figure 1: Insulin-reactive T cells in NOD mice.
Figure 2: Type B T cells are diabetogenic.
Figure 3: Intra-islet DCs pulsed with secretory granules present insulin peptides.
Figure 4: Secretory granules contain proteolytic fragments of the insulin β-chain in NOD Rag1−/− islets.

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Change history

  • 05 March 2010

    In the version of this article initially published online, some hybridomas in Figure 3 were misidentified. The correct text for Figure 3c is “type A (4F7) and type B (2D10 and 1.7) hybridomas” and the correct text for Figure 3e,f is “type B (2D10; e) and type A (4F7; f) hybridomas.” The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

We thank P. Bittner and K. Frederick for technical assistance; R. Belizaire and M. Colonna for comments on the manuscript; M. Gross and H. Rohrs for mass spectrometry; K. Green for electron microscopy; G.S. Eisenbarth and N. Abiru (University of Colorado) for the M12.C3.G7β9-23 cell line; and E. Leiter (Jackson Laboratory) for NIT-1 cells. Supported by National Institutes of Health (AI024742, DK058177 and P60DK20579), the Juvenile Diabetes Research Foundation (JDRF 1-2007-731) and the Kilo Diabetes and Vascular Research Foundation.

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Author notes

  1. Matteo G Levisetti

    Present address: Present address: Merck, Rahway, New Jersey, USA.,

  2. James F Mohan and Matteo G Levisetti: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri, USA

    James F Mohan, Matteo G Levisetti, Boris Calderon, Jeremy W Herzog, Shirley J Petzold & Emil R Unanue

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  1. James F Mohan
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Contributions

J.F.M., M.G.L. and E.R.U. designed and evaluated the experimental work; J.F.M., M.G.L. and J.W.H. did most of the cellular experiments; B.C. did immunofluorescence and confocal microscopy; S.J.P. isolated insulin granules for mass spectrometry and quantified insulin content in granules; and J.F.M. and E.R.U. wrote the manuscript.

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Correspondence to Emil R Unanue.

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The authors declare no competing financial interests.

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Mohan, J., Levisetti, M., Calderon, B. et al. Unique autoreactive T cells recognize insulin peptides generated within the islets of Langerhans in autoimmune diabetes. Nat Immunol 11, 350–354 (2010). https://doi.org/10.1038/ni.1850

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