CD40 on T cells interacts with CD154 to promote autoimmune diabetes (101.7)

Abstract Type 1 diabetes is caused by the autoimmune destruction of pancreatic beta cells mediated by self-reactive CD4 T cells. Our objective in this study was to determine how CD40 on autoreactive CD4 T cells contributes to their pathogenicity. BDC-5.2.9 is a highly diabetogenic CD4 T cell clone and expresses the costimulatory molecule CD40 which can interact with CD154, also expressed on T cells. To investigate signaling through CD40 on T cells, we produced a variant of the diabetogenic T cell clone BDC-5.2.9 expressing a dominant-negative (DN) form of the CD40 molecule. In vitro, we demonstrated that activated T cells express both CD40 and CD154 on their surface and that these two molecules interact when on the same cell. Engagement of CD154 on activated T cells with CD40 on resting T cells resulted in activation of bystander CD40-positive T cells. Transactivation did not occur when clones were transduced with CD40DN, indicating that CD40 engagement on T cells was necessary for transactivation. Furthermore, when the CD40DN variant of BDC-5.2.9 was tested in vivo, none of the recipients developed diabetes. Ex vivo analysis of the pancreatic infiltrate after transfer of BDC-5.2.9 CD40DN revealed an overall reduction of cytokines produced by T cells in addition to decreased activation and function of recruited macrophages. Our data suggest that targeting CD40 expressed on T cells could be a potential avenue for immunotherapy in T1D.