Transcriptional complexes formed by NFAT dimers regulate the induction of T cell tolerance

Abstract

In T cells, anergy can be induced after T cell receptor engagement in the absence of costimulation. Under these conditions, the expression of a specific set of anergy-associated genes is activated. Several lines of evidence suggest that nuclear factor of activated T cells (NFAT) proteins may regulate the expression of many of those genes; however, the nature of the complexes responsible for the induction of this new program of gene expression is unknown. Here, we show that transcriptional complexes formed by NFAT homodimers are directly responsible for the activation of at least two anergy-inducing genes, Grail and Caspase3. Our data shows that Grail expression is activated by direct binding of NFAT dimers to the Grail promoter at two different sites. Consequently, a mutant NFAT protein with impaired ability to dimerize is not able to induce an unresponsive state in T cells. Our results not only identify a new biological function for NFAT dimers but also reveal the different nature of NFAT-containing complexes that induce anergy versus those that are activated during a productive immune response. These data also establish a basis for the design of immunomodulatory strategies that specifically target each type of complex.

The Transcription Factor NFAT1 Participates in the Induction of CD4+T Cell Functional Exhaustion during Plasmodium yoelii Infection

“…NFAT1 participates in the regulation of different programs of T cell inactivation, including T cell anergy and regulatory T cell-mediated suppression of CD4 ϩ T helper cells (13)(14)(15). Similar to anergic cells, exhausted T cells show reduced responses to antigen stimulation.…”

“…During acute activation of T cells, concomitant induction of Fos and Jun in response to the activation of MAPK-regulated pathways results in the expression of many activation-induced genes that present NFAT/AP-1 composite bind- ing sites in the regulatory regions (33,34). However, in response to suboptimal activation, inefficient activation of AP-1 results in the expression of anergy-associated genes, which may feature sites that bind NFAT1 dimer in their promoters or enhancers (15). We still do not know specifically which genes NFAT1 may directly control during exhaustion of CD4 ϩ T cells.…”

“…However, expression of a mutant, constitutively active NFAT1 protein unable to interact with AP-1 has been recently shown to induce the expression of many genes associated with the exhausted phenotype in in vitro-cultured CD4 ϩ and CD8 ϩ T cells (26). Given that NFAT1 monomers have limited transcriptional activity (15), it is tempting to speculate that exhaustion-specific complexes containing NFAT1 and other transcription factors might be responsible for the expression of a distinct program in exhausted T cells. Several other transcription factors have been reported to contribute to the expression of exhaustion-associated genes, including Eomes and Blimp-1 (8, 31, 35, 36).…”

“…Though NFAT proteins were originally described as regulators of activation-induced cytokine expression, the functions regulated by NFAT in T cells now include not only positive but also negative programs that hinder T cell activation (12). For instance, the transcription factor NFAT1 controls the induction of programs of gene expression that allow for the regulatory T cell (Treg)-mediated suppression of CD4 ϩ T cell activation and mediate the induction of CD4 ϩ T cell anergy, a state of functional inactivation that bears phenotypic similarity with T cell exhaustion (13)(14)(15). Clonal T cell anergy occurs as a consequence of suboptimal stimulation, and it is characterized by a unique transcriptional program driven, at least in part, by NFAT1 (9,12,16).…”

Tle4 Regulates Epigenetic Silencing of Gamma Interferon Expression during Effector T Helper Cell Tolerance

“…Anergic T cells fail to proliferate and produce IL-2 when restimulated, even in the presence of costimulation (39,40). In CD4 ϩ T cells, anergy is established as a consequence of the expression of a specific set of anergy-related genes that are transcribed in a calcium/NFAT-and Egr2-dependent manner in response to tolerizing stimuli (2,(41)(42)(43). Initial characterizations of anergic T cells identified a blockade in the Ras/mitogen-activated protein (MAP) kinase signaling pathway (12,44).…”