The T cell CD6 receptor operates a multitask signalosome with opposite functions in T cell activation

• Published in: The Journal of experimental medicine Vol. 218; no. 2
• Main Authors: Mori, Daiki, Grégoire, Claude, Voisinne, Guillaume, Celis-Gutierrez, Javier, Aussel, Rudy, Girard, Laura, Camus, Mylène, Marcellin, Marlène, Argenty, Jérémy, Burlet-Schiltz, Odile, Fiore, Frédéric, Gonzalez de Peredo, Anne, Malissen, Marie, Roncagalli, Romain, Malissen, Bernard
• Format: Journal Article
• Language: English
• Published: Rockefeller University Press 01-02-2021
• Subjects: Immunology; Life Sciences
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20201011

To determine the respective contribution of the LAT transmembrane adaptor and CD5 and CD6 transmembrane receptors to early TCR signal propagation, diversification, and termination, we describe a CRISPR/Cas9–based platform that uses primary mouse T cells and permits establishment of the composition of their LAT, CD5, and CD6 signalosomes in only 4 mo using quantitative mass spectrometry. We confirmed that positive and negative functions can be solely assigned to the LAT and CD5 signalosomes, respectively. In contrast, the TCR-inducible CD6 signalosome comprised both positive (SLP-76, ZAP70, VAV1) and negative (UBASH3A/STS-2) regulators of T cell activation. Moreover, CD6 associated independently of TCR engagement to proteins that support its implication in inflammatory pathologies necessitating T cell transendothelial migration. The multifaceted role of CD6 unveiled here accounts for past difficulties in classifying it as a coinhibitor or costimulator. Congruent with our identification of UBASH3A within the CD6 signalosome and the view that CD6 constitutes a promising target for autoimmune disease treatment, single-nucleotide polymorphisms associated with human autoimmune diseases have been found in the Cd6 and Ubash3a genes.