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J Immunol. 2014 Sep 15;193(6):2651-60. doi: 10.4049/jimmunol.1401196. Epub 2014 Aug 6.

Selective phosphorylation of the Dlg1AB variant is critical for TCR-induced p38 activation and induction of proinflammatory cytokines in CD8+ T cells.

Author information

  • 1Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095;
  • 2Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095;
  • 3Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095; Amgen, Thousand Oaks, CA 91320; and.
  • 4Department of Psychology, University of California, Los Angeles, Los Angeles, CA 90095.
  • 5Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095; cmiceli@ucla.edu.

Abstract

CD8(+) T cells respond to TCR stimulation by producing proinflammatory cytokines, and destroying infected or malignant cells through the production and release of cytotoxic granules. Scaffold protein Discs large homolog 1 (Dlg1) specifies TCR-dependent functions by channeling proximal signals toward the activation of p38-dependent proinflammatory cytokine gene expression and/or p38-independent cytotoxic granule release. Two Dlg1 variants are expressed in CD8(+) T cells via alternative splicing, Dlg1AB and Dlg1B, which have differing abilities coordinate TCR-dependent functions. Although both variants facilitate p38-independent cytotoxicity, only Dlg1AB coordinates p38-dependent proinflammatory cytokine expression. In this study, we identify TCR-induced Dlg1 tyrosine phosphorylation as a key regulatory step required for Dlg1AB-mediated p38-dependent functions, including proinflammatory cytokine expression. We find that Dlg1AB but not Dlg1B is tyrosine phosphorylated by proximal tyrosine kinase Lck in response to TCR stimulation. Furthermore, we identify Dlg1 tyrosine 222 (Y222) as a major site of Dlg1 phosphorylation required for TCR-triggered p38 activation and NFAT-dependent expression of proinflammatory cytokines, but not for p38-independent cytotoxicity. Taken together, our data support a model where TCR-induced phosphorylation of Dlg1 Y222 is a key point of control that endows Dlg1AB with the ability to coordinate p38 activation and proinflammatory cytokine production. We propose blocking Dlg1AB phosphorylation as a novel therapeutic target to specifically block proinflammatory cytokine production but not cytotoxicity.

Copyright © 2014 by The American Association of Immunologists, Inc.

PMID:
25098293
[PubMed - indexed for MEDLINE]
PMCID:
PMC4157853
Free PMC Article
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