The kinase LCK and CD4/CD8 co-receptors are crucial components of the T cell antigen receptor (TCR) signaling machinery, leading to key T cell fate decisions. Despite decades of research, the roles of CD4-LCK and CD8-LCK interactions in TCR triggering in vivo remain unknown. In this study, we created animal models expressing endogenous levels of modified LCK to resolve whether and how co-receptor-bound LCK drives TCR signaling. We demonstrated that the role of LCK depends on the co-receptor to which it is bound. The CD8-bound LCK is largely dispensable for antiviral and antitumor activity of cytotoxic T cells in mice; however, it facilitates CD8+ T cell responses to suboptimal antigens in a kinase-dependent manner. By contrast, the CD4-bound LCK is required for efficient development and function of helper T cells via a kinase-independent stabilization of surface CD4. Overall, our findings reveal the role of co-receptor-bound LCK in T cell biology, show that CD4- and CD8-bound LCK drive T cell development and effector immune responses using qualitatively different mechanisms and identify the co-receptor-LCK interactions as promising targets for immunomodulation.

Division of Rheumatology Rosalind Russell and Ephraim P Engleman Arthritis Research Center Department of Medicine University of California San Francisco CA USA

Institute for Hygiene and Applied Immunology Center for Pathophysiology Infectiology and Immunology Medical University of Vienna Vienna Austria

Institute for Medical Microbiology Immunology and Hygiene Technical University of Munich Munich Germany

Laboratory of Adaptive Immunity Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Mikrobiologisches Institut Klinische Mikrobiologie Immunologie und Hygiene Universitätsklinikum Erlangen Friedrich Alexander Universität Erlangen Nürnberg Erlangen Germany

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