期刊
EUROPEAN JOURNAL OF IMMUNOLOGY
卷 34, 期 5, 页码 1488-1497出版社
WILEY
DOI: 10.1002/eji.200324703
关键词
T cell tolerance; T cell receptor; auto-aggressive T cells; regulatory T cells; autoimmunity
类别
The generation of auto-aggressive T cells involves failure of central or peripheral tolerance. We previously demonstrated that peripheral CD4(lo)CD40(+) 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, CD4(lo)CD40(+) 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 Valpha3.2(+) and Valpha8.3(+) T cells. Furthermore, peripheral Valpha3.2(+)CD40(+) T cells induce diabetes in NOD.scid recipients while Valpha8.3(+) T cells or Valpha3.2(+)-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 Valpha expansion promotes diabetes.
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