LRCH1 deficiency enhances LAT signalosome formation and CD8+ T cell responses against tumors and pathogens
Menée in vitro et à l'aide d'un modèle murin, cette étude démontre que la déficience de la protéine LRCH1 améliore la formation du signalosome de la protéine LAT et la réponse des lymphocytes T CD8+ contre les tumeurs et les agents pathogènes
Improving cytotoxicity, proliferation, and infiltration ability of CD8+ T cells is critical in T cell immunotherapies against tumors. This study has identified LRCH1 as a negative regulator of LAT-mediated TCR signal transduction, as LRCH1 inhibits LAT signalosome formation and facilitates the endocytosis of LAT on the plasma membrane. LRCH1-deficient CD8+ T cells are more proliferative and effective at pathogen control and tumor elimination. Importantly, CRISPR-Cas9–mediated knockout of LRCH1 in human T cells also increases IFN-γ production, cell proliferation, and migration ability in vitro. These data suggest LRCH1 as a potential target to improve CD8+ T cell responses against tumors and pathogens.CD8+ T cells play pivotal roles in eradicating pathogens and tumor cells. T cell receptor (TCR) signaling is vital for the optimal activation of CD8+ T cells. Upon TCR engagement, the transmembrane adapter protein LAT (linker for activation of T cells) recruits other key signaling molecules and forms the “LAT signalosome” for downstream signal transduction. However, little is known about which functional partners could restrain the formation of the LAT signalosome and inhibit CD8+ cytotoxic T lymphocyte (CTL)-mediated cytotoxicity. Here we have demonstrated that LRCH1 (leucine-rich repeats and calponin homology domain containing 1) directly binds LAT, reduces LAT phosphorylation and interaction with GRB2, and also promotes the endocytosis of LAT. Lrch1−/− mice display better protection against influenza virus and Listeria infection, with enhanced CD8+ T cell proliferation and cytotoxicity. Adoptive transfer of Lrch1−/− CD8+ CTLs leads to increased B16-MO5 tumor clearance in vivo. Furthermore, knockout of LRCH1 in human chimeric antigen receptor (CAR) T cells that recognize the liver tumor-associated antigen glypican-3 could improve CAR T cell migration and proliferation in vitro. These findings suggest LRCH1 as a potential translational target to improve T cell immunotherapy against infection and tumors.The RNA-sequencing data reported in this paper have been deposited in the Gene Expression Omnibus under accession no. GSE150634.