G12 family have been known to modulate a variety of cellular events such as cell migration, B cell activation and maturation, cytokine production, and cell differentiation In particular, G alpha 12 modulates IgG production, thus induces IgG antibody-mediated immune responses However, It is largely unknown whether G alpha l2 is required for T cell-mediated immune functions In this study, we investigated the effects of Ga12 in the activation and differentiation of CD4(+) T cells. While PMA plus ionomycin induced equal levels of IL-2 production in WT and G alpha 12-deficient lymphocytes, TCR-triggered IL-2 production was significantly attenuated in G alpha 12 KO lymphocytes In particular, CD4(+) T cells and effector Th cells lacking of G alpha 12 revealed diminished IL-2 production, but not IFN gamma production, upon TCR stimulation In addition, supplement of IL-2 preferentially induced G alpha 12-deficient CD4(+) T cells into Th2 and Th17 cells; however, the expression of specific transcription factors was unchanged in G alpha 12 KO Th cells. While IL-2 expression was still diminished by the re-stimulation with anti-CD3, PMA plus ionomycin restored IL-2 production in G alpha 12-deficient Th1 and Th2 cells These results suggest that G alpha 12 may be a critical signaling molecule in TCR-induced IL-2 production and also relay a signal to suppress Th2 and Th17 cell differentiation (C) 2010 Elsevier Inc All rights reserved