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 Blood, 2 July 2009, Vol. 114, No. 1, pp. 74-84.
Prepublished online as a Blood First Edition Paper on April 28, 2009; DOI 10.1182/blood-2008-09-177832.

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IMMUNOBIOLOGY

The importance of Src homology 2 domain-containing leukocyte phosphoprotein of 76 kilodaltons sterile-{alpha} motif domain in thymic selection and T-cell activation

Shudan Shen1, Jasmine Lau1, Minghua Zhu1, Jianwei Zou1, Deirdre Fuller1, Qi-jing Li1, and Weiguo Zhang1

1 Department of Immunology, Duke University Medical Center, Durham, NC

The Src homology 2 domain–containing leukocyte phosphoprotein of 76 kilodaltons (SLP-76) is a cytosolic adaptor protein essential for thymocyte development and T-cell activation. It contains a sterile-{alpha} motif (SAM) domain, 3 phosphotyrosine motifs, a proline-rich region, and a Src homology 2 domain. Whereas the other domains have been extensively studied, the role of the SAM domain in SLP-76 function is not known. To understand the function of this domain, we generated SLP-76 knockin mice with the SAM domain deleted. Analysis of these mice showed that thymocyte development was partially blocked at the double-positive to single-positive transition. Positive and negative thymic selection was also impaired. In addition, we analyzed T-cell receptor (TCR)–mediated signaling in T cells from these mutant mice. TCR-mediated inositol 1,4,5-triphosphate production, calcium flux, and extracellular signal-regulated kinase activation were decreased, leading to defective interleukin-2 production and proliferation. Moreover, despite normal association between Gads and SLP-76, TCR-mediated formation of SLP-76 microclusters was impaired by the deletion of the SAM domain. Altogether, our data demonstrated that the SAM domain is indispensable for optimal SLP-76 signaling.


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