Reciprocal function of Gαi2 and Gαi3 in graft-versus-host disease

Abstract

This study delineates specific functions of Gai2 and Gai3 in T cell mobilization during the development of graft-versus-host disease (GVHD) and reveals reciprocal effects of these two G proteins on the onset and morbidity of the disease. A deletion of Gai2 hampered trafficking of pathogenic T cells from secondary lymphoid tissues to inflammatory sites and sufficiently prevented GVHD. In contrast, a severer disease was induced in mice adoptively transferred with Gαi3-deficient T cells than those mice transferred with wild-type T cells. In agreement with this, pathogenic Gαi2-/- T cells displayed a defect in response to CXCL10, CXCL11, and CCL5, whereas lack of Gαi3 augmented T effector cell chemotaxis induced by CXCL10 and CXCL11 and resulted in their preference of homing to the liver and colon. Absence of either Gai also abrogated sphingosince-1-phosphate (S1P)-mediated inhibition of T cell chemokinesis and facilitated T cell homing and expansion in the spleen and mesenteric lymph nodes at the early phase of GVHD development, which is another key determinant in the severity and early onset of the disease in the mice infused with Gαi3-/- T cells. These observations underscore interplay between Gαi2 and Gαi3 and potentially provide a novel strategy to prevent GVHD by blocking T cell homing at early stages and T effector cell trafficking at later time points. © 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.