The Yins of T Cell Activation

Transcription factors activated in response to T cell receptor (TCR) signaling include nuclear factor of activated T cells (NFAT) family, which is highly phosphorylated and thereby maintained in the cytoplasm of resting T cells, the nuclear factor NF-κB, which is kept in the cytoplasm of resting cells through its association with the inhibitor protein IκB, and activating protein–1 (AP-1), which is only transcribed after TCR stimulation. Negative regulators of TCR signaling can be divided into two groups: Class 1 regulators help maintain the quiescent state of unstimulated T cells, whereas class 2 regulators are themselves transcriptionally induced in response to TCR signaling and serve to limit and terminate the activating signal. Class 1 regulators include the autoinhibitory domain of the phosphatase calcineurin; IκB and its transcriptional activators Foxj1 and Foxo3a; and various transcriptional coregulators that inhibit interleukin-2 (IL-2) production. Class 2 regulators include the calcipressins, which, like NFATp and NFAT4 are feedback inhibitors of calcineurin-NFAT signaling, IκB, and the mitogen-activated protein kinase (MAPK) phosphatases, which inhibit MAPK signaling and thus the nuclear localization of AP-1 components. The potentially destructive power of the immune response necessitates tight regulation of T cell activation, and this STKE review, with three figures, no tables, and 56 references, concerns negative regulators of T cell signaling. These negative regulators can be divided into two groups: Class 1 regulators help maintain the quiescent state of unstimulated T cells, whereas class 2 regulators are themselves transcriptionally induced in response to T cell signaling and serve to limit and terminate the activating signal.