Peripheral CD4loCD40+ auto‐aggressive T cell expansion during insulin‐dependent diabetes mellitus

Open Access
Publisher Website
Google Scholar
Abstract
The generation of auto‐aggressive T cells involves failure of central or peripheral tolerance. We previously demonstrated that peripheral CD4loCD40+ T cells give rise to pathogenic T cells in the non‐obese diabetic (NOD) model. Here we show that peripheral CD4+CD40+ T cells from diabetic or pre‐diabetic NOD mice induce insulin‐dependent diabetes mellitus. Consistent with breach of peripheral tolerance, CD4loCD40+ T cells expand with age in NOD mice but not in MHC‐matched non‐obese resistant (NOR) or BALB/c controls. Suggestive of a causal role for CD40 in autoimmunity, blocking CD40–CD154 interactions early during NOD development prevents autoaggressive T cell expansion while promoting increases in CD4+CD25+ regulatory T cells. Importantly, CD40 signals promote expansion of Vα3.2+ and Vα8.3+ T cells. Furthermore, peripheral Vα3.2+CD40+ T cells induce diabetes in NOD.scid recipients while Vα8.3+ T cells or Vα3.2+‐depleted T cell populations do not. This is the first demonstration that primary T cells transfer disease with the kinetics of auto‐aggressive T cell clones and that specific TCR Vα expansion promotes diabetes.