Foxp3-independent mechanism by which TGF-β controls peripheral T cell tolerance

Significance

A functional immune system requires a highly diverse repertoire of T cells to optimize protection against foreign pathogens while maintaining tolerance against self-antigens. Two critical pathways in the control of T cell tolerance are the cytokine TGF-β and Foxp3-expressing Treg cells. However, since TGF-β promotes Treg cell development, and Treg cells also produce the cytokine, whether TGF-β and Treg cells are part of the same regulatory module to repress self-reactive T cells or function as distinct pathways remains incompletely understood. Using a mouse model of autoimmune diabetes, this study elucidates a dominant role for a Foxp3-independent mechanism of TGF-β signaling in the regulation of T cell tolerance.

Abstract

Peripheral T cell tolerance is promoted by the regulatory cytokine TGF-β and Foxp3-expressing Treg cells. However, whether TGF-β and Treg cells are part of the same regulatory module, or exist largely as distinct pathways to repress self-reactive T cells remains incompletely understood. Using a transgenic model of autoimmune diabetes, here we show that ablation of TGF-β receptor II (TβRII) in T cells, but not Foxp3 deficiency, resulted in early-onset diabetes with complete penetrance. The rampant autoimmune disease was associated with enhanced T cell priming and elevated T cell expression of the inflammatory cytokine GM-CSF, concomitant with pancreatic infiltration of inflammatory monocytes that triggered immunopathology. Ablation of the GM-CSF receptor alleviated the monocyte response and inhibited disease development. These findings reveal that TGF-β promotes T cell tolerance primarily via Foxp3-independent mechanisms and prevents autoimmunity in this model by repressing the cross talk between adaptive and innate immune systems.