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Impaired TGF- Responses in Peripheral T Cells of Gi2^–/– Mice ¹

Jim Y. Wu, YongZhu Jin^*, Robert A. Edwards^,, Yujin Zhang, Milton J. Finegold and Mei X. Wu^2,*,

^* Wellman Center of Photomedicine, Massachusetts General Hospital, and Department of Dermatology, Harvard Medical School, Boston, MA 02114; Synta Pharmaceuticals, Lexington, MA 02421; Department of Pathology, Baylor College of Medicine, Houston, TX 77030; and Department of Pathology, University of California, Irvine, CA 92697

Null mutation of heterotrimeric G protein 2 inhibitory subunit (Gi2) 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 Gi2 in regulating immune responses, are poorly understood. We show here that peripheral T cells from Gi2-deficient mice do not respond normally to the inhibitory effects of TGF- on proliferation and cytokine production, revealing a previously unappreciated cross-talk between these two signaling pathways. Lack of Gi2 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- stimulation, which appears to be ascribed to differential expression of neither cell surface TGF- receptors nor Smad7. The altered phosphorylation of Smad proteins involves phospholipase C-mediated signaling, a downstream signaling molecule of Gi2, because phospholipase C inhibitors could restore Smad2 and Smad3 phosphorylation in Gi2^–/– T cells at levels comparable to that in wild-type T cells. Moreover, adoptive transfer of Gi2-deficient T cells into immunocompromised mice rendered an otherwise resistant mouse strain susceptible to trinitrobenzesulfonic acid-induced colitis, suggesting that an impaired response of Gi2-deficient T cells to TGF- 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 Gi2 down-regulates immune responses, contributing to the maintenance of mucosal tolerance.

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