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Unique roles of co-receptor-bound LCK in helper and cytotoxic T cells.

Nature immunology (2022-12-24)
Veronika Horkova, Ales Drobek, Darina Paprckova, Veronika Niederlova, Avishek Prasai, Valeria Uleri, Daniela Glatzova, Markus Kraller, Michaela Cesnekova, Sarka Janusova, Eva Salyova, Oksana Tsyklauri, Theresa A Kadlecek, Katerina Krizova, René Platzer, Kilian Schober, Dirk H Busch, Arthur Weiss, Johannes B Huppa, Ondrej Stepanek
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-Phosphotyrosine Antibody, clone 4G10®, clone 4G10®, Upstate®, from mouse
Sigma-Aldrich
Chorionic gonadotropin human, lyophilized powder, vial of ~10,000 IU