Research ArticleImmunology

The costimulatory molecule CD226 signals through VAV1 to amplify TCR signals and promote IL-17 production by CD4+ T cells

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Sci. Signal.  10 Jul 2018:
Vol. 11, Issue 538, eaar3083
DOI: 10.1126/scisignal.aar3083

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VAV1, a T cell hub

The guanine nucleotide exchange factor VAV1 is required for T cell receptor (TCR) signaling and activation of T cells. By analyzing the VAV1 interactome, Gaud et al. found that VAV1 also interacted with the costimulatory molecule CD226. Engagement of CD226 activated VAV1, which in turn enhanced the TCR-dependent production of the proinflammatory cytokine IL-17 by human T cells. A variant of CD226 that is associated with autoimmune diseases stimulated more VAV1 activity and IL-17 production than did wild-type CD226, demonstrating that VAV1-mediated cross-talk between the CD226 and TCR signaling pathways affects both normal and pathological T cell activation.

Abstract

The activation of T cells requires the guanine nucleotide exchange factor VAV1. Using mice in which a tag for affinity purification was attached to endogenous VAV1 molecules, we analyzed by quantitative mass spectrometry the signaling complex that assembles around activated VAV1. Fifty VAV1-binding partners were identified, most of which had not been previously reported to participate in VAV1 signaling. Among these was CD226, a costimulatory molecule of immune cells. Engagement of CD226 induced the tyrosine phosphorylation of VAV1 and synergized with T cell receptor (TCR) signals to specifically enhance the production of interleukin-17 (IL-17) by primary human CD4+ T cells. Moreover, co-engagement of the TCR and a risk variant of CD226 that is associated with autoimmunity (rs763361) further enhanced VAV1 activation and IL-17 production. Thus, our study reveals that a VAV1-based, synergistic cross-talk exists between the TCR and CD226 during both physiological and pathological T cell responses and provides a rational basis for targeting CD226 for the management of autoimmune diseases.

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