T cell differentiation in the thymus is dependent on signaling by both T cell antigen receptors and by cytokine receptors. Our current understanding of how lineage choice is determined in the thymus is built around the concept that signaling by the T cell antigen receptor prevents signaling by cytokine receptors, and that cytokine signaling only occurs after signaling by the T cell antigen receptor has ceased. Despite its central role in T cell development, it is not known how T cell antigen receptor signaling 'desensitizes' the cytokine receptor so that it is no longer able to transmit signals into the cell. Consequently, we have undertaken a systematic examination of the molecular basis by which cytokine receptor signaling is impaired by TCR signals in developing T cells in the thymus and in mature T cells in the periphery. We have discovered that TCR signals upregulate expression of the microRNA mir-17 that targets Janus kinase 1 (Jak1) whose activation initiates IL-7 signal transduction. Unexpectedly, we discovered that Jak1 is an extremely unstable protein which is rapidly degraded in T cells, so that continuous Jak1 protein synthesis is required to maintain Jak1 at levels sufficient to promote IL-7 signal transduction. Thus, by targeting Jak1 mRNA, mir-17 inhibits Jak1 translation and Jak1 protein synthesis, which acutely disrupts IL-7 signaling.
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