LCK–coreceptor association ensures T cell lineage fidelity and maximizes epitope–specific TCR diversity 2153

Description The interaction between the CD4/CD8 coreceptors and LCK 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 coreceptors (LCKFREE mice), we show that influenza A virus (IAV)–derived pMHC–specific CD8 and CD4 T cell responses had a significantly narrowed 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 coreceptors 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–coreceptor association is critical for ensuring T cell lineage fidelity and maximizing antigen–specific T cell repertoire diversity. Funding Sources N.L.G. is supported by an NHMRC Investigator Grant (2017335) and an ARC Discovery Project (DP230102412). J.R. is supported by an NHMRC Investigator Grant (2008981). P.Z. is supported by an ARC DECRA Fellowship (DE230101012).