Understanding the role of NFAT2 transcription factors in T-cell Exhaustion

The transcription factor Nuclear Factor of Activated T-cells (NFAT) plays a key role in determining the fate of a T-cell and is an important target for immune modulation. NFAT drives different programs of gene expression depending on availability of its partner proteins. For instance, in the presence of Activator Protein 1 (AP-1), it drives an effector immune response however, in the absence of AP-1, it drives the exhaustion program. T-cell exhaustion is a state of dysfunction caused due to persistent antigen exposure that occurs in cancer and chronic infections that hinders the ability of T-cell to respond to the antigen. In this study we examine the role of different isoforms of NFAT2 in T-cell exhaustion by overexpressing constitutively active NFAT2 isoforms in CD8+ T-cells. We show that contrary to what is believed, the short NFAT2 isoform (NFAT2alphaA) is not able to drive the exhaustion program by itself, as it does not impair CD8+ T-cells ability to produce IL2. Additionally, we show that the early steps of the T-cell exhaustion program elicited by NFAT proteins, assessed as differences in protein expression and CD8+ T cell function, do not require chromatin rearrangement. Our study provides a valuable insight into the role of NFAT2 proteins in the T-cell exhaustion program