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.

The onset of autoimmunity in experimental rodent models and patients frequently correlates with a lymphopenic state. In this condition, the immune system has evolved compensatory homeostatic mechanisms that induce quiescent naive T cells to proliferate and differentiate into memory-like lymphocytes even in the apparent absence of antigenic stimulation. Because memory T cells have less stringent requirements for activation than naive cells, we hypothesized that autoreactive T cells that arrive to secondary lymphoid organs in a lymphopenic environment could differentiate and bypass the mechanisms of peripheral tolerance such as those mediated by self-antigen cross-presentation. Here, we show that lymphopeniadriven proliferation and differentiation of potentially autoreactive CD8 ؉ T cells into memory-like cells is not sufficient to induce selfreactivity against a pancreatic antigen. Induction of an organ-specific autoimmunity required antigen-specific CD4 ؉ T cell help. Notably, we found that this function could be accomplished by memory-like CD4 ؉ T cells generated in vivo through lymphopenia-induced proliferation. These helper cells promoted the further differentiation of memorylike CD8 ؉ T cells into effectors in response to antigen cross-presentation, resulting in their migration to the tissue of antigen expression where autoimmunity ensued. Thus, the cooperation of self-reactive memory-like CD4 ؉ and CD8 ؉ T cells under lymphopenic conditions overcomes cross-tolerance resulting in autoimmunity.autoimmunity ͉ T cell help ͉ T cell homeostasis

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