NF-AT, Nuclear factor of activated T cell

The signaling complex formed around the TCR and the branching pathways that emanate from it resemble the mechanisms used by the growth factors. However, the destinations of these pathways are not all clear. The PLC-y pathway (DAG, IP3, and elevation of intracellular free Ca2+) leads to activation of the phosphatase calcineurin, which activates the transcription factor NF-AT (nuclear factor of activated T cells). This is essential for clonal expansion of T cells because of its pivotal role in the induction of IL-2 expression. NF-AT requires the assistance of the activator protein 1 (AP-1) complex in order to drive expression of IL-2. 

Figure 32.4. Cyclosporin A (CsA) disruption of signal transduction pathways leading to IL-2 production. CsA binds to cyclophilin in the cytoplasm. The complex disrupts at least two signaling pathways, decreasing activation of transcription factors AP-1 and NF-AT that lead to activation of genes involved in cytokine production. See text for detailed explanation. Abbreviations TCR, T-cell receptor PLC, phospholipase C IP3, inositol triphosphate PKC, protein kinase C DAG, diacylglycerol NF-AT, nuclear factor of activation PI, phophati-dylinositol PC, phosphatidylcholine.

CSA inhibits T-cell proliferation by inhibiting the production of IL-2 and other cytokines by T cells (see Fig. 87-1). CSA binds to cy-clophihn, a cytoplasmic immunophilin. The CSA-cyclophilin complex inhibits the action of calcineurin, an enzyme that activates the nuclear factor of activated T cells (NF-AT), which is, in turn, responsible for the transcription of several key cytokines necessary for T-cell activity, including IL-2. IL-2 is a potent growth factor for T cells, responsible for activation and clonal expansion. 

Mechanism of action These peptide antibiotics interfere with T cell function by binding to immunophyllins, small cytoplasmic proteins that play critical roles in T cell responses to TCR activation and to cytokines. Cyclosporine binds to cyclophilin and tacrolimus binds to FK-binding protein (FKBP), both complexes inhibiting calcineurin, a cytoplasmic phosphatase. Calcineurin regulates the ability of the nuclear factor of activated T cells (NF-AT) to translocate to the nucleus and increase the production of cytokines. Cyclophilin and tacrolimus both inhibit the production of cytokines that normally occurs in response to TCR activation. Sirolimus also binds to FKBP, inhibiting the re-... 

Both lymphotactin and fractalkine are expressed in an activation-dependent manner. The expression of lymphotactin is upregulated by phorbol ester and concanavalin 1 in T-cells isolated from peripheral blood (Middel et al., 2001). It can be inhibited by anti-inflammatory steroid dexamethasone or immunosuppressive drugs such as cyclosporine A and FK506 (Middel et al., 2001). These agents also regulate the expression of lymphotactin receptor XCRl on T-cells in a manner similar to the regulation of lymphotactin expression. The nuclear factor of activated T-cells (NF-AT) family s transcription factors are likely to be involved in the activation-induced expression and cyclosporine A-dependent inhibition of lymphotactin (Yoshida et al., 1999). 

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