Peripheral CD4loCD40+ auto-aggressive T cell expansion during insulin-dependent diabetes mellitus.
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 V alpha 3.2(+) and V alpha 8.3(+) T cells. Furthermore, peripheral V alpha 3.2(+)CD40(+) T cells induce diabetes in NOD.scid recipients while V alpha 8.3(+) T cells or V alpha 3.2(+)-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 V alpha expansion promotes diabetes.
Waid
Dan M
DM
Webb-Waring Institute and Departmentof Medicine, University of Colorado Health Sciences Center, Denver, 80262, USA.
Vaitaitis
Gisela M
GM
Wagner
David H
DH
D000818:Animals; D015551:Autoimmunity / Q000276:immunology / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D019013:CD40 Antigens / Q000378:metabolism*; D023201:CD40 Ligand / Q000378:metabolism; D002455:Cell Division / Q000502:physiology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D010179:Pancreas / Q000378:metabolism
D019013:CD40 Antigens; D023201:CD40 Ligand