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T Cell Ig and Mucin Domain-1-Mediated T Cell Activation Requires Recruitment and Activation of Phosphoinositide 3-Kinase¹

Anjali J. de Souza^*, Jean S. Oak, Ryan Jordanhazy^*, Rosemarie H. DeKruyff, David A. Fruman and Lawrence P. Kane^2,*

^* Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; Department of Molecular Biology and Biochemistry, and Center for Immunology, University of California, Irvine, CA 92697; and Division of Immunology, Children’s Hospital Boston, Harvard Medical School, Boston, MA 02115

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the National Institutes of Health (AI67544 to L.P.K., AI50831 to D.A.F., P01 AI054456 and HL069507 to R.H.D., and T32 AI60573 to J.S.O.).

² Address correspondence and reprint requests to Dr. Lawrence P. Kane, University of Pittsburgh, Biomedical Science Tower E-1056, 200 Lothrop Street, Pittsburgh, PA 15261. E-mail address: lkane{at}pitt.edu

³ Abbreviations used in this paper: TIM, T cell Ig and mucin domain; k.o., knockout; IP, immunoprecipitation; stim, stimulated; unstim, unstimulated; m, mouse.