The costimulatory molecule CD226 signals through VAV1 to amplify TCR signals and promote IL 17 production by CD4+ T cells
VAV1 mediates cross talk between the CD226 and TCR signaling pathways to enhance production of the proinflammatory cytokine IL 17. 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. 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.
Science Signaling