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

Abstract

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.

Contribution of Evolutionary Selected Immune Gene Polymorphism to Immune-Related Disorders: The Case of Lymphocyte Scavenger Receptors CD5 and CD6

“…Upon CD5 and CD6 receptor ligation and phosphorylation, several downstream intracellular signal transducers are engaged. The multiple interactors recruited to the CD5 signalosome (SHP-1, Ras-GAP, Cbl-b, UBASH3A, ANKRD13A and CK2) finally end up down-modulating lymphocyte activation [ 42 , 43 , 44 , 45 , 46 ]. As for the CD6 signalosome, the reported interactors (SLP-76, ZAP-70, VAV1, GRB2, GRAP2, GRK, GADS, TSAd, UBASH3A, SHIP1, ARHGAP45 and Syntenin) end up providing co-inhibitory or co-stimulatory functions [ 46 , 47 , 48 , 49 , 50 ].…”

ARHGAP45 controls naïve T‐ and B‐cell entry into lymph nodes and T‐cell progenitor thymus seeding

“…T cells express more than 20 GAPs, and the function and mechanism of action of most of them remain to be elucidated (Stein & Ruef, 2019). We recently identified the ARHGAP45 GAP among the signaling protein complexes that assemble in mouse primary T cells (Voisinne et al , 2019; Mori et al , 2021). ARHGAP45, also known as HMHA1 (human minor histocompatibility antigen 1), has been first described in human and comprises an N‐terminal BAR domain followed by a C1 and a RHO GAP domain (de Kreuk et al , 2013).…”

Adapting T Cell Receptor Ligand Discrimination Capability via LAT

“…A recent proteomic study revealed that the LAT signalosome exhibits dynamic time-dependent interaction relationships with the transmembrane receptors CD5-and CD6-assembled signalosomes (81). According to that study, the LAT signalosome mostly plays a dominant role as an activating signaling pathway node, as characterized by its ability to activate SOS-ERK and PLCg1-NFAT pathways (81). However, unlike the LAT signalosome, the CD5 signalosome is enriched with many proteins with inhibitory functions, including Cbl-b and Ubash3A (81).…”

“…According to that study, the LAT signalosome mostly plays a dominant role as an activating signaling pathway node, as characterized by its ability to activate SOS-ERK and PLCg1-NFAT pathways (81). However, unlike the LAT signalosome, the CD5 signalosome is enriched with many proteins with inhibitory functions, including Cbl-b and Ubash3A (81). Interestingly, the CD6-induced signalosome functions as a buffering zone, competing interacting proteins with either the inhibitory CD5 signalosome or with the stimulatory LAT signalosome.…”

“…Interestingly, the CD6-induced signalosome functions as a buffering zone, competing interacting proteins with either the inhibitory CD5 signalosome or with the stimulatory LAT signalosome. SLP76, GRB2, and GRB2 related adaptor protein 2 (GRAP2) can be associated with either the LAT signalosome or CD6 signalosome, whereas SOS, PLCg1 and hematopoietic progenitor kinase 1 (HPK1) can only associate with the LAT signalosome (81). Competition of these shared interactors influences the relative ratio of active LAT signalosome versus that of the CD6 complex.…”