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Summary 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.

To maintain the size of T cell pools throughout life, homeostatic mechanisms regulate both survival and proliferation, which is achieved by IL-7 and TCR signaling. IL-7 (through lymphopenia-induced proliferation/LIP) can also mediate expansion of autoreactive clones leading to the onset of autoimmune disease or enhance effector function against tumors and viruses. In the setting of chronic HIV infection, CD4 T cell depletion and the increased availability of IL-7 triggers LIP that occurs in an inflammatory environment rich in Type-I IFNs; we hypothesized that this pathway could contribute to the immune activation leading to CD4 T cell depletion and CD8 T cell pool expansion. Accordantly, we found that genes associated with γ c cytokines and Type-I IFN signaling were differentially expressed in CD4 and CD8 T cells from chronic HIV infected patients. Using a lymphopenic murine model, we present new evidence that, in vivo, IL-7 differentially regulated the expression of the total-Signal Transducer and Activator of Transcription 1 (t-STAT1) in CD4 and CD8 T cells undergoing LIP and in so doing enhanced CD4 T cell responsiveness to Type-I IFN. In this setting, chronic treatment with IFN- α led to decreased CD4 T cell counts and CD8 T cell expansion. This interplay between IL-7 and Type-I IFN might be advantageous in immunity against pathogens, however chronic stimulation of this pathway could be deleterious for CD4 T cell homeostasis and may contribute to the aberrant immune activation and eventual CD4 T cell depletion observed during HIV infection.