The Transcription Factor NFAT Promotes Exhaustion of Activated CD8 + T Cells

Abstract

SUMMARY During persistent antigen stimulation, CD8+ T cells show a gradual decrease in effector function, referred to as exhaustion, which impairs responses in the setting of tumors and infections. Here we demonstrate that the transcription factor NFAT controls the program of T cell exhaustion. When expressed in cells, an engineered form of NFAT1 unable to interact with AP-1 transcription factors diminished T cell receptor (TCR) signaling, increased the expression of inhibitory cell surface receptors, and interfered with the ability of CD8+ T cells to protect against Listeria infection and attenuate tumor growth in vivo. We defined the genomic regions occupied by endogenous and engineered NFAT1 in primary CD8+ T cells, and showed that genes directly induced by the engineered NFAT1 overlapped with genes expressed in exhausted CD8+ T cells in vivo. Our data show that NFAT promotes T cell anergy and exhaustion by binding at sites that do not require cooperation with AP-1.

Inhibition of FOXP3/NFAT Interaction Enhances T Cell Function after TCR Stimulation

“…NFAT proteins interact with Fos-Jun (AP-1) transcription factors to form cooperative NFAT/AP-1 complexes that are critical for the induction of cytokine genes and other activation-associated genes. However, it has been demonstrated very recently that the transcription factor NFAT may promote T cell anergy and exhaustion by binding at sites that do not require cooperation with AP-1 (49). The ability to participate in multiple transcriptional complexes allows NFAT to contribute to different transcriptional programs and T cell plasticity depending on the cell type and signaling context in which it is activated (13).…”

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

“…At least two mediators of TCR signals, SPRY2 and NFAT, have been identified as factors involved in supporting the establishment of exhaustion in CD8 ϩ T cells (25,26). Our data indicate that NFAT1 is also a central regulator of the induction of exhaustion in CD4 ϩ T cells.…”

“…These data suggest that NFAT proteins other than NFAT1 may also participate in the regulation of the expression of these exhaustion-associated genes. Indeed, NFAT2 has been shown to regulate PD-1 expression in activated T cells and to cooperate with NFAT1 in the expression of PD-1 and LAG-3 in CD8 ϩ T cells exhausted by LCMV infection (26,32). However, the disconnect between the continued expression of these two molecules and the decreased exhausted phenotype seen in CD4 ϩ T cells may support the idea that Plasmodium infection-induced expression of PD-1 and LAG-3 may be required (4) but not sufficient to induce a full exhausted phenotype.…”

“…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.…”

Modulation of Cytokine Production and Transcription Factors Activities in Human Jurkat T Cells by Thymol and Carvacrol

“…NFAT-1 and NFAT-2, two prevalent members of this family expressed in immune cells, play an important role in regulating a large number of inducible genes through the immune responses. 15 NFAT proteins are involved in regulating transcription of numerous inducible genes in immune cells including IL-2, IFN-γ, IL-4, IL-5, TNF-α and CD40L that regulate cell differentiation, proliferation, apoptosis and survival. 16 NFAT/AP-1 cooperation is necessary for the majority of these genes to undergo expression.…”