| Nuclear factor of activated T-cells 1 (NFAT1) is a transcription factor that is involved in both T cell activation as well as T cell anergy and drives distinct context-dependent transcriptional programs. Though the role of NFAT1 in activation is dispensable, NFAT1 is essential for multiple mechanisms of peripheral tolerance, including the functional inactivation of anergic CD4 + T cells, as well as the suppression of CD4+ T cells by regulatory T cells (Tregs). Due to the central role of NFAT1 in suppressing T cell responses in these contexts, we investigated whether NFAT1 plays a role in inhibition of CD4+ T cell function following chronic stimulation. First, we established an in vitro model of T cell exhaustion achieved by repetitive stimulation of CD4+ T cells by co-culture with antigen presenting cells loaded with cognate antigen. We then tested the role of NFAT1 in an in vivo model of exhaustion using Plasmodium yoelii, a murine-tropic parasite that has been shown to cause exhaustion of CD4+ T cells. In each of these models of T cell exhaustion, NFAT1 was required for full downregulation of function evidenced by cytokine secretion and/or proliferation. Using microarray analysis, we also found that NFAT1 drives a subset of exhaustion-associated genes in chronically stimulated cells. In addition, adoptive transfer of CD4 + T cells lacking NFAT1 expression drove greater antibody responses to Plasmodium yoelii expressing their cognate antigen and also delayed death due to lethal Plasmodium infection. These results show that NFAT1 drives a portion of the T cell exhaustion transcriptional program and that its contribution to establishing the T cell exhaustion phenotype has consequences for both the ability of CD4+ T cells to make cytokines and proliferate, as well as in their helper function in promoting antibody responses. Furthermore, we have demonstrated that NFAT1 can mediate suppression of CD4+ T cell function in T cells in the context of an infection, in addition to its previously established role as an important effector in maintaining peripheral tolerance of CD4+ T cells. |
