The conventional view on T cell development posits that signals from the same T cell receptor (TCR) determines both positive and negative selection as well as lineage choice into mature CD4+ helper and CD8+ cytotoxic cells. The precise mechanism how this is achieved is still under dispute but it has been proposed that either quantitative or qualitative differences in TCR signaling would account for the different outcomes of lineage choice. In contrast to such views, here we show that TCR signaling alone is not sufficient to determine cell fate of developing thymocytes, and that CD4/CD8 lineage choice requires additional cues by cytokines such as interleukin-7 (IL-7). Using conditional deletion of immediate downstream signaling molecules of the IL-7 receptor, we demonstrate that IL-7 induced cytokine signals are required for CD8 lineage choice and for the differentiation into mature CD8+ cytotoxic T cells in vivo. Our data establish a previously unappreciated role for in vivo IL-7 and other gamma c-cytokines in CD8 lineage commitment of immature thymocytes, which is consistent with the kinetic signaling model of T cell lineage choice. We have recently also identified an unexpected role for non-gamma c-cytokines (IL-6, TSLP, and IFNgamma) in CD8 lineage commitment and are actively analyzing their mode of action during positive selection in the thymus.
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