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

Archive ouverte

Gaud, Guillaume | Roncagalli, Romain | Chaoui, Karima | Bernard-Cadenat, Isabelle | Familiades, Julien | Colacios, Celine | Kassem, Sahar | Monsarrat, Bernard | Burlet-Schiltz, Odile | Peredo, Anne Gonzalez, De | Malissen, Bernard | Saoudi, Abdelhadi

Edité par CCSD ; American Association for the Advancement of Science (AAAS) -

International audience. 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.

• Description
• Sujet/Public
• Outil
• Outil d'anticipation
• Mémoire et thèse
• Gestion