Transforming growth factor-β signaling to T cells inhibits autoimmunity during lymphopenia-driven proliferation

T cell specific deletion of the Transforming growth factor-β (TGF-β) receptor mediated by CD4-cre leads to early onset lethal autoimmune disease that cannot be controlled by regulatory T cells. However, when we delete the receptor using distal Lck (dLck) promoter driven cre, adult mice in which the majority of peripheral CD4(+) and CD8(+) T cells lacked the TGF-β receptor, showed no signs of autoimmunity. Due to their heightened response to weak T cell receptor stimuli, when transferred into lymphopenic recipients, naive TGF-β unresponsive T cells exhibited dramatically enhanced proliferation, effector differentiation, and induced lymphoproliferative disease. We propose that TGF-β signaling controls self-reactivity of peripheral T cells but in the absence of TGF-β signals, an added trigger, such as lymphopenia, is required to drive overt autoimmune disease.