Research ArticleImmunology

The Chemokine CXCL12 Generates Costimulatory Signals in T Cells to Enhance Phosphorylation and Clustering of the Adaptor Protein SLP-76

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Sci. Signal.  30 Jul 2013:
Vol. 6, Issue 286, pp. ra65
DOI: 10.1126/scisignal.2004018

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The CXC chemokine CXCL12 mediates the chemoattraction of T cells and enhances the stimulation of T cells through the T cell receptor (TCR). The adaptor SLP-76 [Src homology 2 (SH2) domain–containing leukocyte protein of 76 kD] has two key tyrosine residues, Tyr113 and Tyr128, that mediate signaling downstream of the TCR. We investigated the effect of CXCL12 on SLP-76 phosphorylation and the TCR-dependent formation of SLP-76 microclusters. Although CXCL12 alone failed to induce SLP-76 cluster formation, it enhanced the number, stability, and phosphorylation of SLP-76 microclusters formed in response to stimulation of the TCR by an activating antibody against CD3, a component of the TCR complex. Addition of CXCL12 to anti-CD3–stimulated cells resulted in F-actin polymerization that stabilized SLP-76 microclusters in the cells’ periphery at the interface with antibody-coated coverslips and increased the interaction between SLP-76 clusters and those containing ZAP-70, the TCR-associated kinase that phosphorylates SLP-76, as well as increased TCR-dependent gene expression. Costimulation with CXCL12 and anti-CD3 increased the extent of phosphorylation of SLP-76 at Tyr113 and Tyr128, but not that of other TCR-proximal components, and mutation of either one of these residues impaired the CXCL12-dependent effect on SLP-76 microcluster formation, F-actin polymerization, and TCR-dependent gene expression. The effects of CXCL12 on SLP-76 microcluster formation were dependent on the coupling of its receptor CXCR4 to Gi-family G proteins (heterotrimeric guanine nucleotide–binding proteins). Thus, we identified a costimulatory mechanism by which CXCL12 and antigen converge at SLP-76 microcluster formation to enhance T cell responses.

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