Lck Availability during Thymic Selection Determines the Recognition Specificity of the T Cell Repertoire

Thymic selection requires signaling by the protein tyrosine kinase Lck to generate T cells expressing αβ T cell antigen receptors (TCR). For reasons not understood, the thymus selects only αβTCR that are restricted by major histocompatibility complex (MHC)-encoded determinants. Here, we report that Lck proteins that were coreceptor associated promoted thymic selection of conventionally MHC-restricted TCR, but Lck proteins that were coreceptor free promoted thymic selection of MHC-independent TCR. Transgenic TCR with MHC-independent specificity for CD155 utilized coreceptor-free Lck to signal thymic selection in the absence of MHC, unlike any transgenic TCR previously described. Thus, the thymus can select either MHC-restricted or MHC-independent αβTCR depending on whether Lck is coreceptor associated or coreceptor free. We conclude that the intracellular state of Lck determines the specificity of thymic selection and that Lck association with coreceptor proteins during thymic selection is the mechanism by which MHC restriction is imposed on a randomly generated αβTCR repertoire. [Display omitted] •Lck sequestration during thymic selection is the basis for T cell MHC restriction•Coreceptor-independent Lck generates an MHC-independent TCR repertoire•Transgenic MHC-independent αβTCR are selected in the absence of thymic MHC•CD155 is the thymic selecting ligand for CD155-specific MHC-independent TCR A mutant Lck that cannot associate with either CD4 or CD8 coreceptors reveals thymic selection of MHC-independent T cells, suggesting that "MHC restriction" is not an innate property of TCRs but is instead a selective process that relies on Lck kinase status.