NFAT proteins: key regulators of T-cell development and function

Abstract

The nuclear factor of activated T cells (NFAT) family of transcription factors consists of five members, NFAT1–NFAT5, which share a conserved DNA-binding domain that is structurally related to the REL-homology domain of REL and nuclear factor-κB family members. T cells express three of the four calcium-regulated NFAT proteins: NFAT1, NFAT2 and NFAT4. These proteins are key regulators of T-cell activation, differentiation and development. In T cells, NFAT proteins are activated following T-cell receptor (TCR) ligation. Increases in calcium that are induced by TCR engagement activate calcineurin, which causes NFAT dephosphorylation and nuclear translocation. Several kinases, including casein kinase 1 (CK1) and glycogen-synthase kinase 3 (GSK3), are also involved in the regulation of NFAT nuclear import and export. In activated T cells, NFAT proteins synergize with activator protein 1 (AP1) transcription factors at composite sites that are located in the promoters and enhancers of many cytokine genes. Interactions of NFAT proteins with transcription factors other than AP1 have been described for different gene promoters in T cells and can induce the activation or inhibition of NFAT activity. NFAT1 can also bind as a homodimer to NF-κB-binding motifs. The results obtained from the analysis of single and double gene-knockout mice indicate that, although there is a certain level of redundancy in the NFAT family of transcription factors, some specific T-cell functions might be regulated by specific NFAT proteins. Experimental evidence indicates that, during T-cell development, calcium–calcineurin–NFAT signalling is a key regulator of positive selection. NFAT2 and NFAT4 might also control thymocyte proliferation and survival. NFAT proteins cooperate with lineage-specific transcription factors to determine pathways of T helper (T_H)-cell differentiation into T_H1- or T_H2-cell populations. Programmes of gene expression that lead to T-cell inactivation and are crucial to maintain T-cell tolerance are also regulated by NFAT proteins in the absence of AP1 cooperation. Disrupting function-specific NFAT interactions with other transcription factors might provide new targets for the development of more specific therapeutic approaches to control immune responses during autoimmunity or graft rejection.