Zhang, Justin B., Chaurasia, Priyanka, Nguyen, Angela, Huang, Zijian, Nguyen, Trang T., Xu, Hui, Tran, Mai T., Reid, Hugh H., Jones, Claerwen M., Schattgen, Stefan A., Thiele, Daniel, Thomas, Paul G., Rientjes, Jeanette, Good-Jacobson, Kim L., Ruscher, Roland, Littler, Dene R., Rossjohn, Jamie, Zareie, Pirooz, and La Gruta, Nicole L. (2025) LCK–co-receptor association ensures T cell lineage fidelity and maximizes epitope-specific TCR diversity. Science Immunology, 10 (104). eadp5016.

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Abstract

The interaction between the CD4/CD8 co-receptors and LCK (an Src family tyrosine kinase) is thought to augment T cell activation upon recognition of peptide-loaded major histocompatibility complexes (pMHCs). How this interaction influences antigen-specific T cell development is unclear however, as is its impact on naïve and immune antigen-specific T cell repertoires. In mice expressing mutated endogenous LCK unable to bind co-receptors (LCK^FREE mice), we show that influenza A virus (IAV)–derived pMHC-specific CD8 and CD4 T cell responses had a significantly narrowed T cell receptor (TCR) repertoire, favoring high-affinity TCRs. This narrowing was established during T cell development and was exacerbated after viral infection. The dissociation of LCK from co-receptors also resulted in the redirection of CD4-fated T cells to the CD8 lineage, with expanded pMHCII-specific cytotoxic CD8 T cells observed after IAV infection. Thus, LCK–co-receptor association is critical for ensuring T cell lineage fidelity and maximizing antigen-specific T cell repertoire diversity.

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