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Sci Signal. 2018 Jul 10;11(538). pii: eaar3083. doi: 10.1126/scisignal.aar3083.

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

Author information

1
Centre de Physiopathologie de Toulouse Purpan, Université de Toulouse, CNRS, Inserm, Toulouse 31300, France.
2
Centre d'Immunologie de Marseille-Luminy, Aix-Marseille Université, Inserm, CNRS, 13288 Marseille, France.
3
Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS UMR 5089, 31077 Toulouse Cedex, France.
4
Centre d'Immunophénomique, Aix-Marseille Université, Inserm, CNRS, 13288 Marseille, France.
5
Centre de Physiopathologie de Toulouse Purpan, Université de Toulouse, CNRS, Inserm, Toulouse 31300, France. abdelhadi.saoudi@inserm.fr.

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.

PMID:
29991650
DOI:
10.1126/scisignal.aar3083

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