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J Biol Chem, Vol. 273, Issue 31, 19914-19921, July 31, 1998

Association of p59^fyn with the T Lymphocyte Costimulatory Receptor CD2
BINDING OF THE Fyn Src HOMOLOGY (SH) 3 DOMAIN IS REGULATED BY THE Fyn SH2 DOMAIN

Huamao Lin^§, Jill E. Hutchcroft, Christopher E. Andoniou^¶, Malek Kamoun, Hamid Band^¶, and Barbara E. Bierer^**

From the  Department of Pediatric Oncology, Dana-Farber Cancer Institute, ^§ Committee on Immunology, Division of Medical Sciences, and ^¶ Lymphocyte Biology Section, Department of Rheumatology and Immunology, Brigham and Woman's Hospital, Boston, Massachusetts 02115, the  Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, and the ^** Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115

Human CD2 is a 50-55-kDa cell surface receptor specifically expressed on the surface of T lymphocytes and NK cells. Stimulation of human peripheral blood T cells with mitogenic pairs of anti-CD2 monoclonal antibodies (mAbs) is sufficient to induce interleukin-2 production and T cell proliferation in the absence of an antigen-specific signal through the T cell receptor. CD2 has been shown previously to associate physically with the Src family protein-tyrosine kinases p56^lck and p59^fyn. We now report that stimulation of T cells with mitogenic pairs of anti-CD2 mAbs enhanced the association of the Fyn polypeptide with the CD2 complex, whereas stimulation with single anti-CD2 mAb had minimal effect. Using glutathione S-transferase (GST) fusion proteins, we found that CD2 bound to the Src homology (SH) 3 domain of Fyn. Interestingly, the CD2-Fyn association was negatively regulated by the Fyn SH2 domain; CD2 bound poorly to GST fusion proteins expressing both the SH2 and SH3 domains of Fyn. However, the inhibitory effect of the Fyn SH2 domain on binding of the Fyn SH3 domain to CD2 was relieved by peptides containing a phosphorylated YEEI sequence that bound directly to the Fyn SH2 domain. In addition, we found that the ability of the Fyn SH2 domain to precipitate tyrosine-phosphorylated proteins, including the CD3 chain, was enhanced after T cell stimulation with mitogenic pairs of CD2 mAbs. Finally, overexpression of a mutated Fyn molecule, in which the ability of the Fyn SH2 domain to bind phosphotyrosine-containing proteins was abrogated, inhibited CD2-induced transcriptional activation of the nuclear factor of activated T cells (NFAT), suggesting a functional involvement of the Fyn SH2 domain in CD2-induced T cell signaling. We thus propose that stimulation through the CD2 receptor leads to the tyrosine phosphorylation of intracellular proteins, including CD3 itself, which in turn bind to the Fyn-SH2 domain, allowing the direct association of the Fyn SH3 domain with CD2 and the initiation of downstream signaling events.

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