TCR signaling antagonizes rapid IP-10-mediated transendothelial migration of effector memory CD4+ T cells.
Human microvascular endothelial cells (ECs) constitutively express MHC class II in peripheral tissues, the function of which remains unknown. In vitro assays have established that the recognition of EC MHC class II can affect cytokine expression, proliferation, and delayed transendothelial migration of allogeneic memory, but not naive, CD4+ T cells. Previously, we have shown that effector memory CD4+ T cells will rapidly transmigrate in response to the inflammatory chemokine IFN-gamma-inducible protein-10 (IP-10) in a process contingent upon the application of venular levels of shear stress. Using two models that provide polyclonal TCR signaling by ECs in this flow system, we show that TCR engagement antagonizes the rapid chemokine-dependent transmigration of memory CD4+ T cells. Inhibitor studies suggest that TCR signaling downstream of Src family tyrosine kinase(s) but upstream of calcineurin activation causes memory CD4+ T cell arrest on the EC surface, preventing the transendothelial migration response to IP-10.
Manes
Thomas D
TD
Department of Pathology, Yale University School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Avenue, New Haven, CT 06520, USA.
Shiao
Stephen L
SL
Dengler
Thomas J
TJ
Pober
Jordan S
JS
D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D019703:Calcineurin / Q000276:immunology; D002465:Cell Movement / Q000276:immunology*; D002478:Cells, Cultured; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000276:immunology*; D042783:Endothelial Cells / Q000166:cytology / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D018448:Models, Immunological; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D019061:src-Family Kinases / Q000276:immunology
C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D000949:Histocompatibility Antigens Class II; D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma; D019061:src-Family Kinases; D019703:Calcineurin