NFAT pulls the strings during CD4+ T helper cell effector functions

Abstract

The Ca 2؉ dependent transcription factor family known as nuclear factor of activated T cells (NFAT) has been shown to be important in T-cell immune responses. Because NFAT proteins have a weak DNAbinding capacity, they cooperate with other transcription factors at composite sites within the promoters of target genes. Recently, NFAT was shown to also be important for the induction of specific genetic programs that guide the differentiation and effector or regulatory activities of CD4 ؉ T helper subsets via the transcriptional regulation of their lineagespecific transcription factors, specifically T-bet (Th1), Gata3 (Th2), ROR␥t (Th17), and Foxp3 (iTregs). In addition, the NFAT family governs the transcription of several signature cytokines, including their cytokine receptors. Subsequently, the integration of these complex intracellular signal transduction cascades is considered to critically determine the crosstalk between the T-cell receptor and receptors that are activated by both the adaptive and innate immune systems to determine pathways of T helper cell differentiation and function. Here, we carefully review the critical role of the established transcriptional partners and functional outcomes of these NFAT interactions in regard to the effector responses of these clinically relevant CD4 ؉ T helper subsets. IntroductionThe Ca 2ϩ -dependent transcription factor family, known as nuclear factor of activated T cells (NFATs), originally identified by Shaw et al, 1 regulates not only T lymphocytes but also a large number of growth factors, cytokines, and cell-to-cell interaction molecules essential for the morphogenesis, development, and function of many cell types and organs. 2,3 In T lymphocytes, NFAT proteins govern gene expression that regulates T-cell development, activation, differentiation, as well as the induction and maintenance of T-cell tolerance. [4][5][6] Briefly, the NFAT family consists of 5 family members that all share a highly conserved DNA-binding domain: NFAT1 (NFATc2; NFATp), NFAT2 (NFATc1; NFATc), NFAT3 (NFATc4); NFAT4 (NFATc3; NFATx), and NFAT5 (TonEBP; OREBP). In T lymphocytes, 2 or more splice forms of NFAT1, 2, and 4 are present, encoding the following domains 4 : the NFAT homology region containing a transactivation (TAD-A) and regulatory domain (docking sites for calcineurin and the NFAT kinases), the Relhomology region with the N-terminal DNA-binding domain that is also involved in protein-to-protein interactions, and the C terminal domain. The Rel-homology region contains the DNA-binding loop that confers base-specific recognition, and the C terminal domain, which makes contact only with the DNA phosphate backbone. Activation of the NFAT pathway occurs after receptor activation coupled to the calcium-signaling pathway. 7 Calcium release from intracellular stores, together with cytosolic calcium, binds calmodulin, which in turn activates the calmodulin-dependent phosphatase calcineurin. NFAT proteins are dephosphorylated by activated calcineurin, leading to their nuclear translocation...

Nuclear Factor of Activated T Cells Regulates Neutrophil Recruitment, Systemic Inflammation, and T-Cell Dysfunction in Abdominal Sepsis

“…However, in this study we found no impact of NFAT inhibition on bacterial burden in blood, peritoneal cavity, lung, and spleen 24 h after CLP induction. In this context, it is important to note that NFAT has been well established as a promoter of T-cell maturation and differentiation (54). At first glance, our findings showing that inhibition of NFAT protects T-cell survival and cytokine formation might appear counterintuitive.…”

RNA-Seq analysis of high NaCl-induced gene expression

“…2A). The results are counterintuitive because NFAT and IRF have been shown to synergize with each other in regulating in gene expression, and the two binding sites are partially overlapped at the nucleotide level (6,10). This prompted us to determine the enrichment of the IRF1 binding site at the promoter region (Ϫ10 to 2 kb around the transcription start site) of up-and downregulated genes in WT and null cells.…”

The NAMPT Promoter Is Regulated by Mechanical Stress, Signal Transducer and Activator of Transcription 5, and Acute Respiratory Distress Syndrome–Associated Genetic Variants

“…However, in response to 18% CS, reductions in STAT5 expression significantly attenuated SNP-dependent enhanced NAMPT promoter activity with either NAMPT variant. Because GR acts as a transcriptional coactivator for STAT5 and enhances STAT5-dependent transcription (32) and because STAT5 combines with nuclear factor of activated T cells to promote Foxp3 transcription (33), the effects of the 2948G/T and 22,422A/G SNPs may synergize with STAT5 to significantly enhance NAMPT transcription with the influence of these cotranscription factors during pathological stress. Together, these studies demonstrated that STAT5 significantly regulates NAMPT transcription under pathological mechanical stress.…”