Reciprocal function of Galphai2 and Galphai3 in graft-versus-host disease.
This study delineates specific functions of Galphai2 and Galphai3 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 Galphai2 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 Galphai3-deficient T cells than those mice transferred with wild-type T cells. In agreement with this, pathogenic Galphai2(-/-) T cells displayed a defect in response to CXCL10, CXCL11, and CCL5, whereas lack of Galphai3 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 Galphai 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 Galphai3(-/-) T cells. These observations underscore interplay between Galphai2 and Galphai3 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.
Wellman Center of Photomedicine, Massachusetts General Hospital, and Department of Dermatology, Harvard Medical School, Boston, MA, USA.
Yong Zhu
YZ
Jin
Brian D
BD
Thompson
Zho Yan
ZY
Zhou
Yineng
Y
Fu
Lutz
L
Birnbaumer
Mei X
MX
Wu
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D018925:Chemokines / Q000276:immunology / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte; D003106:Colon / Q000276:immunology / Q000473:pathology; D005260:Female; D044385:GTP-Binding Protein alpha Subunits / Q000378:metabolism*; D006086:Graft vs Host Disease / Q000276:immunology* / Q000378:metabolism*; D008099:Liver / Q000276:immunology / Q000473:pathology; D008221:Lymphoid Tissue / Q000276:immunology; D008246:Lysophospholipids / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology
D018925:Chemokines; D044385:GTP-Binding Protein alpha Subunits; D008246:Lysophospholipids; C060506:sphingosine 1-phosphate; D013110:Sphingosine