Impaired TGF-β Responses in Peripheral T Cells of Gαi2−/− Mice

Null mutation of heterotrimeric G protein α2 inhibitory subunit (Gαi2) induces Th1-skewed hyperimmune responses in the colon, leading to chronic colitis and the development of colonic adenocarcinoma. However, the underlying molecular mechanisms and cellular basis, in particular, for the role of Gαi2 in regulating immune responses, are poorly understood. We show here that peripheral T cells from Gαi2-deficient mice do not respond normally to the inhibitory effects of TGF-β on proliferation and cytokine production, revealing a previously unappreciated cross-talk between these two signaling pathways. Lack of Gαi2 resulted in decreased phosphorylation of Smad2 and Smad3 in T cells at the basal levels as well as at the late but not early phase of TGF-β stimulation, which appears to be ascribed to differential expression of neither cell surface TGF-β receptors nor Smad7. The altered phosphorylation of Smad proteins involves phospholipase C-mediated signaling, a downstream signaling molecule of Gαi2, because phospholipase C inhibitors could restore Smad2 and Smad3 phosphorylation in Gαi2−/− T cells at levels comparable to that in wild-type T cells. Moreover, adoptive transfer of Gαi2-deficient T cells into immunocompromised mice rendered an otherwise resistant mouse strain susceptible to trinitrobenzesulfonic acid-induced colitis, suggesting that an impaired response of Gαi2-deficient T cells to TGF-β may be one of the primary defects accounting for the observed colonic Th1-skewed hyperimmune responses. These findings shed new lights on the molecular and cellular basis of how Gαi2 down-regulates immune responses, contributing to the maintenance of mucosal tolerance.