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Down-regulation of diabetogenic CD4+ T cells by a soluble dimeric peptide–MHC class II chimera

Nature Immunology volume 3, pages 383–391 (2002)Cite this article

Abstract

Type 1 diabetes is an organ-specific autoimmune disease that is mediated by autoreactive T cells. We show here that administration of a soluble dimeric peptide–major histocompatibility complex (pMHC) class II chimera (DEF) to prediabetic double-transgenic mice prevents the onset of disease or, in animals that are already diabetic, restores normoglycemia. The antidiabetogenic effects of DEF rely on the induction of anergy in splenic autoreactive CD4+ T cells via alteration of early T cell receptor signaling and stimulation of interleukin 10–secreting T regulatory type 1 cells in the pancreas. Soluble dimeric pMHC class II may be useful in the development of immunospecific therapies for type 1 diabetes.

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Figure 1: DEF protects dTg mice against diabetes.
Figure 2: DEF induces anergy in splenic TCR-Tg T cells.
Figure 3: Inhibition of ZAP-70 phosphorylation in DEF-treated dTg mice.
Figure 4: DEF does not affect the development of TCR-Tg thymic precursors.
Figure 5: Assessment of diabetogenicity for DEF-anergized T cells.
Figure 6: DEF stimulates regulatory IL-10–secreting CD4+ T cells in the pancreas.
Figure 7: DEF up-regulates the expression of CD62L on pancreatic TCR-Tg T cells and favors migration to the peripheral lymphoid organs.

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Acknowledgements

We thank A. Miller for helpful discussions. Supported by grants from the Juvenile Diabetes Foundation International, Alexander & Alexandrine L. Sinsheimer Foundation and from the National Institutes of Health (grant 1R55DK55744 to S. C. and grants 1R01DK061927 and 1R21DK61326 to T.-D. B.).

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Authors and Affiliations

  1. Department of Microbiology, Mount Sinai School of Medicine, New York, 10029, NY, USA

    Sofia Casares, Alicia Hurtado & Teodor-Doru Brumeanu

  2. Diabetes Center, Children's Hospitals and Clinics, St. Paul, Minneapolis, 55102, MN, USA

    Robert C. McEvoy

  3. Institut Necker, INSERM 373, Paris, France

    Adelaida Sarukhan

  4. Dana-Farber Cancer Institute, Boston, MA, USA

    Harald von Boehmer

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Correspondence to Sofia Casares.

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Casares, S., Hurtado, A., McEvoy, R. et al. Down-regulation of diabetogenic CD4+ T cells by a soluble dimeric peptide–MHC class II chimera. Nat Immunol 3, 383–391 (2002). https://doi.org/10.1038/ni770

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