NFAT transcription factors in control of peripheral T cell tolerance

Abstract

The Ca ++ -regulated calcineurin/NFAT cascade is one of the crucial signalling pathways that controls adaptive immunity. However, a number of novel experimental data suggest that, in addition to their role in T cell activation, NFATc transcription factors play also a decisive role in the generation of peripheral tolerance against self-antigens. This function of NFATc factors is mediated by controlling activation-induced cell death and clonal anergy of T helper cells and the activity of regulatory T cells. The multi-functional role of NFATc proteins characterize these transcription factors as key regulators of immunological tolerance and, if dysregulated, of development of autoimmune diseases. Introduction: Peripheral tolerance and NFAT transcription factorsThe primary function of the adaptive immune system of vertebrates is to defend an organism against invading microorganisms and parasites. In addition to the complex molecular mechanisms creating a strong defence system against foreign antigens, several mechanisms have been developed to tolerate self-antigens. With the appearance of the adaptive immune system in jawed fish [1], such tolerance mechanisms have evolved in parallel to suppress the generation of autoimmune and allergic diseases. For the generation of T cell tolerance, one can distinguish two main mechanisms: central tolerance and peripheral tolerance. A comprehensive review of central T cell tolerance has recently been published by Bruno Kyewski and Ludger Klein [2]. Therefore, in this brief review we will focus on mechanisms of peripheral T cell tolerance mediated by the induction of anergy, by suppression through CD4 + CD25 + regulatory T cells (Treg) and by activationinduced cell death (AICD), which, to a large extent, are all controlled by NFAT transcription factors.NFAT (nuclear factor of activated T cells) transcription factors were originally described as nuclear proteins that bind to and control the activity of the interleukin 2 (IL-2) promoter and further lymphokine promoters/ enhancers in T lymphocytes. However, NFAT factors are also expressed in other cell types and regulate the activity of numerous genes that control the generation of cardiac septa and valves in embryonic heart, the formation of blood vessels, the outgrowth of neuronal axons and the differentiation of osteoclasts during bone formation [3][4][5]. Among the five members of the NFAT factor family (Fig. 1A), the activity of four NFATc proteins (NFATc1, c2, c3 and c4) is controlled by the Ca ++ /calmodulin-dependent phosphatase calcineurin (CN) that, by dephosphorylating numerous sites within the regulatory region of NFAT, stimulates cytosolicnuclear translocation and subsequent DNA binding of NFAT factors [3][4][5]. CN is a direct target of two immunosuppressants, cyclosporin A (CsA) and FK506, which, when complexed with immunophilins, can bind to CN and inhibit its enzymatic activity. Without active CN, the activity of NFAT factors is suppressed, T cell activation is blocked and rejection of transplanted organs can be preve...

The dendritic cell life cycle

“…This particular phenomenon has been accounted for by the downregulation of NFATmediated FasL expression, [26][27][28][29] leading to a lack of activated T-and B-cell apoptosis. 23 Consistent with this interpretation, NFATc2/c3 double-deficient T cells restimulated in vitro with anti-CD3 antibody do not die after 6 to 8 h, indicating that, unlike wild-type T cells, they do not undergo activation-induced cell death (AICD). 30 A similar proapoptotic function of NFATc2 has been described for Burkitt's lymphoma cells following B-cell receptor stimulation.…”

“…Before our demonstration of a proapoptotic role for NFATc2/c3 in activated cDCs, a similar proapoptotic role had already been reported for these two isoforms in activated T and B lymphocytes. 23 NFATc2-deficient mice do indeed have considerably larger numbers of peripheral lymphocytes than wild-type mice. 24,25 This phenotype is even more marked in mice lacking both NFATc2 and c3, which also had markedly enlarged peripheral lymphoid organs.…”

Orai1-NFAT Signalling Pathway Triggered by T Cell Receptor Stimulation

“…NFAT consists of four homologous NFAT1 (NFATc2), NFAT2 (NFATc1), NFAT3 (NFATc4), and NFAT4 (NFATc3) (Hogan et al, 2003;Macian, 2005;Serfling et al, 2006;Wu et al, 2007). Most of the NFAT genes are expressed in lymphocytes, however NFAT1 is predominantly expressed in naïve, single-positive T cells.…”

E3 ubiquitin ligases in T‐cell tolerance

“…In addition to anergy intrinsic to the T cell, NFAT proteins have been implicated in the regulation of gene expression of two other major mechanism of peripheral tolerance -T reg suppression and activation-induced cell death [22]. For instance, it has been reported that NFAT1 interacts with the transcription factor Foxp3 in the epigenetic regulation of genes involved in T reg differentiation.…”

“…Following costimulation, NFAT cooperates with the AP-1 family of transcription factors, and possibly others, to induce the expression of activation-associated genes [20,21]. In contrast to normal activation, anergic conditions appear to lead to an unbalanced activation of NFAT and translocation of NFAT proteins to the nucleus in the absence of AP-1, thereby inducing the expression of anergy-associated genes [15].In addition to anergy intrinsic to the T cell, NFAT proteins have been implicated in the regulation of gene expression of two other major mechanism of peripheral tolerance -T reg suppression and activation-induced cell death [22]. For instance, it has been reported that NFAT1 interacts with the transcription factor Foxp3 in the epigenetic regulation of genes involved in T reg differentiation.…”