Damage control, rather than unresponsiveness, effected by protective DX5+ T cells in autoimmune diabetes

Abstract

The progression of autoimmune diabetes is regulated. We examined here the cellular controls exerted on disease that developed in the BDC2.5 T cell receptor–transgenic model. We found that all BDC2.5 mice with a monoclonal, β cell–reactive, T cell repertoire developed diabetes before 4 weeks of age; transfer of splenocytes from young standard NOD (nonobese diabetic) mice into perinatal monoclonal BDC2.5 animals protected them from diabetes. The protective activity was generated by CD4+ αβ T cells, which operated for a short time at disease initiation, could be partitioned according to DX5 cell surface marker expression and split into two components. Protection did not involve clonal deletion or anergy of the autoreactive BDC2.5 cells, permitting their full activation and attack of pancreatic islets; rather, it tempered the aggressiveness of the insulitic lesion and the extent of β cell destruction.

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Figure 1: Exclusive expression of the transgene-encoded TCR accelerates diabetes in BDC2.5 mice.
Figure 2: CD4+ αβ T cells protect B/Ro mice from diabetes.
Figure 3: Not the usual suspects.
Figure 4: Surface expression of the DX5 distinguishes two populations required for optimal protection.
Figure 5: DX5+ and NK1.1+ CD4+ T cells are distinct populations.
Figure 6: IL-4 and IL-10 are required by protective cells, but cross-complement.
Figure 7: Protective cells do not prevent insulitis; they merely control it.
Figure 8: Phenotypic alterations in aggressive and protective populations.

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Acknowledgements

We thank L. Lanier, K. Rajewsky, F. Luhder and P. Hoglund for reagents and discussion; C. Waltzinger and C. Ebel for cell sorting; T. Ding for histology; and P. Michel and M. Gendron for maintaining the mice. Supported by institute funds from the INSERM, the CNRS, the Hopital Universitaire de Strasbourg and the Juvenile Diabetes Foundation International (A. G.).

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Correspondence to Diane Mathis or Christophe Benoist.

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Gonzalez, A., Andre-Schmutz, I., Carnaud, C. et al. Damage control, rather than unresponsiveness, effected by protective DX5+ T cells in autoimmune diabetes. Nat Immunol 2, 1117–1125 (2001). https://doi.org/10.1038/ni738

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