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Originally published In Press as doi:10.1074/jbc.M403538200 on August 3, 2004

J. Biol. Chem., Vol. 279, Issue 41, 43117-43125, October 8, 2004
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Negative Regulation of T Cell Receptor Signaling by Siglec-7 (p70/AIRM) and Siglec-9*

Yuzuru Ikehara, Sanae Kabata Ikehara, and James C. Paulson{ddagger}

From the Departments of Molecular Biology and Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037

Siglec-7 (p70/AIRM) and Siglec-9 are "CD33"-related siglecs expressed on natural killer (NK) cells and subsets of peripheral T cells. Like other inhibitory NK cell receptors, they contain immunoglobulin receptor family tyrosine-based inhibitory motifs in their cytoplasmic domains, and Siglec-7 has been demonstrated to negatively regulate NK cell activation. Based on reports of the presence of these siglecs on T cells, we sought to determine if they are capable of modulating T cell receptor (TCR) signaling using Jurkat T cells stably and transiently transfected with Siglec-7 or Siglec-9. Following either pervanadate stimulation or TCR engagement, both Siglecs exhibited increased tyrosine phosphorylation and recruitment of SHP-1. Effects of Siglec-7 and -9 were also evident in downstream events in the signaling pathway. Both siglecs reduced phosphorylation of Tyr319 on ZAP-70, known to play a pivotal role in up-regulation of gene transcription following TCR stimulation. There was also a corresponding decreased transcriptional activity of nuclear factor of activated T cells (NFAT) as determined using a luciferase reporter gene. Like all siglecs, Siglec-7 and -9 recognize sialic acid-containing glycans of glycoproteins and glycolipids as ligands. Mutation of the conserved Arg in the ligand binding site of Siglec-7 (Arg124) or Siglec-9 (Arg120) resulted in reduced inhibitory function in the NFAT/luciferase transcription assay, suggesting that ligand binding is required for optimal inhibition of TCR signaling. The combined results demonstrate that both Siglec-7 and Siglec-9 are capable of negative regulation of TCR signaling and that ligand binding is required for optimal activity.

Received for publication, March 31, 2004 , and in revised form, July 26, 2004.

* This work was supported in part by National Institutes of Health Grant AI050143 and a Research fellowship (to Y. I.) from the Uehara Memorial Foundation. 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.

{ddagger} To whom correspondence should be addressed: The Scripps Research Institute, Mail drop: MEM L71, 10550 North Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-784-9634; Fax: 858-784-9690; E-mail: jpaulson{at}scripps.edu.


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