LRCH1 deficiency enhances LAT signalosome formation and CD8⁺ T cell responses against tumors and pathogens

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 117; no. 32; pp. 19388 - 19398
• Main Authors: Liu, Chang, Xu, Xiaoyan, Han, Lei, Wan, Xiaopeng, Zheng, Lingming, Li, Chunyang, Liao, Zhaohui, Xiao, Jun, Zhong, Ruiyue, Zheng, Xin, Wang, Qiong, Li, Zonghai, Chen, Hualan, Wei, Bin, Wang, Hongyan
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 11.08.2020
• Subjects: Adapter proteins; Adapters; Adaptor Proteins, Signal Transducing - metabolism; Adoptive transfer; Animals; Antigen (tumor-associated); Antigens; Biocompatibility; Biological Sciences; Calponin; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - transplantation; Cell activation; Cell adhesion & migration; Cell Movement; Cell proliferation; Cells, Cultured; Chimeric antigen receptors; Cytotoxicity; Cytotoxicity, Immunologic; Endocytosis; GRB2 Adaptor Protein - metabolism; Grb2 protein; Heparan sulfate proteoglycans; Homology; Humans; Immunotherapy; Immunotherapy, Adoptive; Infections; Infections - immunology; Infections - microbiology; Infections - virology; Influenza; Interferon-gamma - metabolism; Leucine; Leukocyte migration; Listeria; Lung Neoplasms - therapy; Lymphocyte Activation; Lymphocytes; Lymphocytes T; Membrane Proteins - metabolism; Mice; Mice, Knockout; Microfilament Proteins - deficiency; Microfilament Proteins - genetics; Microfilament Proteins - metabolism; Pathogens; Phosphorylation; Protein Binding; Receptors; Receptors, Antigen, T-Cell - metabolism; Receptors, Chimeric Antigen - metabolism; Signal Transduction; Signaling; T cell receptors; Toxicity; Tumor cells; Tumors; Viruses; migration; LRCH1; CD8+ T cell; LAT; cytotoxicity
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2000970117

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.