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J. Biol. Chem., Vol. 279, Issue 46, 47783-47791, November 12, 2004

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CD22 Is a Functional Ligand for SH2 Domain-containing Protein-tyrosine Phosphatase-1 in Primary T Cells^*

From the ^aSection of Infection and Immunity, Henry Wellcome Building for Biomedical Research in Wales, Cardiff University, Cardiff CF14 4XX, Wales, United Kingdom, the ^dCancer Biology Program, Division of Hematology-Oncology, Beth Israel-Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, and the ^hDepartment of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115

The intracellular Src homology 2 (SH2) domain-containing protein-tyrosine phosphatase (SHP-1) has been characterized as a negative regulator of T cell function, contributing to the definition of T cell receptor signaling thresholds in developing and peripheral mouse T lymphocytes. The activation of SHP-1 is achieved through the engagement of its tandem SH2 domains by tyrosine-phosphorylated proteins; however, the identity of the activating ligand(s) for SHP-1, within mouse primary T cells, is presently unresolved. The identification of SHP-1 ligand(s) in primary T cells would provide crucial insight into the molecular mechanisms by which SHP-1 contributes to in vivo thresholds for T cell activation. Here we present a combination of biochemical and yeast genetic analyses indicating CD22 to be a T cell ligand for the SHP-1 SH2 domains. Based on these observations we have confirmed that CD22 is indeed expressed on mouse primary T cells and capable of associating with SHP-1. Significantly, CD22-deficient T cells demonstrate enhanced proliferation in response to anti-CD3 or allogeneic stimulation. Furthermore, the co-engagement of CD3 and CD22 results in a raising of TCR signaling thresholds hence demonstrating a previously unsuspected functional role for CD22 in primary T cells.

Received for publication, March 2, 2004 , and in revised form, September 3, 2004.

^* This work is supported by Project Grant 065556 from The Wellcome Trust (to R. J. M. and P. B.) and a NATO Collaborative Grant (to R. J. M. and Dr. L. Shultz, The Jackson Laboratory, Bar Harbor, ME). This work is also supported by Grant R01 DK66600 (to B. G. N.) from the National Institutes of Health. 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.

^b Funded jointly by University of Wales College of Medicine and "The Overseas Research Students Awards Scheme" and is currently supported by the Medical Research Council.

^c Supported by a Medical Research Council Research Studentship.

^e A fellow of the Lymphoma Research Foundation (New York).

^f Present address: Washington University School of Medicine, St. Louis, MO 63110.

^g Supported by the Leukaemia Research Fund.

ⁱ Present address: Dept. of Molecular Biotechnology, College of Life and Environmental Sciences, Konkuk University, Seoul 143-701, Korea.

^j To whom correspondence should be addressed. Tel.: 44-29-20742484; Fax: 44-29-20745003; E-mail: matthewsrj{at}cardiff.ac.uk.

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