T cell Ig and mucin domain-1-mediated T cell activation requires recruitment and activation of phosphoinositide 3-kinase.
Ligation of the transmembrane protein T cell Ig and mucin domain (Tim)-1 can costimulate T cell activation. Agonistic Abs to Tim-1 are also capable of inducing T cell activation without additional stimuli. However, little is known about the biochemical mechanisms underlying T cell stimulation or costimulation through Tim-1. We show that a tyrosine in Tim-1 becomes phosphorylated in a lck-dependent manner, whereupon it can directly recruit p85 adaptor subunits of PI3K. This results in PI3K activation, which is required for Tim-1 function. We also provide genetic evidence that p85 expression is required for optimal Tim-1 function. Thus, we describe a pathway from Tim-1 tyrosine phosphorylation to the PI3K signaling pathway, which appears to be a major effector of Tim-1-mediated T cell activation.
de Souza
Anjali J
AJ
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Oak
Jean S
JS
Jordanhazy
Ryan
R
DeKruyff
Rosemarie H
RH
Fruman
David A
DA
Kane
Lawrence P
LP
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D000072596:Hepatitis A Virus Cellular Receptor 1; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis; D019169:Jurkat Cells; D037181:Lectins, C-Type; D008213:Lymphocyte Activation / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011991:Receptors, Virus / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D014162:Transfection; D014443:Tyrosine; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000072596:Hepatitis A Virus Cellular Receptor 1; D007376:Interleukin-2; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D019869:Phosphatidylinositol 3-Kinases; D011991:Receptors, Virus; D014443:Tyrosine; D000099192:CD69 Antigens; C491143:HAVCR1 protein, human