T cell receptor signaling allows the developing thymocyte to undergo positive or negative selection, which is required for the formation of a useful mature T cell repertoire. Recent developments include the finding that much of the Lck kinase (required to initiate T cell signaling) is already in an active configuration before signaling. The analog strength of antigen binding to the T cell receptor binding may be translated into a digital signal by the amount of time the TCR is paired with a co-receptor carrying Lck. Downstream, the cellular localization of MAP kinase signaling is determined by the strength of the signal and in turn predicts positive or negative selection. A novel protein, Themis, is important in crossing the positive selection developmental checkpoint, but its mode of action is still uncertain. Commitment to the CD4 or CD8 lineage is influenced by the amount of ZAP-70 signaling and also by closely regulated responsiveness to intrathymic cytokines such as IL7.
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