Induction of NFATc1 Controls the Fate of Activated T Cells

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Transcription factors of the ‚Nuclear Factor of Activated T Cell‘ (NFAT) family control the activation and effector function of lymphocytes. Inhibition of NFAT by immunosuppresants, such as cyclosporin A or FK506, impairs primarily the inflammatory function of activated T cells, and their overwhelming success in transplantation medicine led to a revolution in medicine. NFAT proteins are activated by a Ca++/calcineurin signaling cascade in the cytosol. In addition to their posttranslational regulation, one of the most prominent NFAT family members, NFATc1, is also regulated at the transcriptional level. Activation of lymphocytes by antigen receptor stimulation induces the expression of a short isoform, NFATc1/aA, which differs structurally and functionally from all other NFAT proteins by individual terminal peptides and its anti-apoptotic properties.We showed previously that the NFATc1/aA induction is controlled by a remote transcriptional enhancer, designated das E2, located within the last intron of the Nfatc1 gene. To determine the physiological role of this regulatory element, we generated a novel transgenic mouse line in which the E2 enhancer can selectively be deleted in T cells. Loss of the E2 impaired the induction of NFATc1/aA resulting in a strong decrease of numerous NFATc1 target genes in activated T cells. In vivo, deletion of E2 not only abrogated germinal center formation and humoral immunity but also perturbed the cellular immune responses to viral infection. Adoptive transfer experiments with virus-specific T cells revealed that the induction of NFATc1/aA prevents the (functional) exhaustion of CD8+ T cells and promotes their survival in chronically infected recipient mice. This specific function of E2 is not only important during viral infection but has also important (clinical) implications for anti-tumor immunity.In this project, we will elucidate the effect of NFATc1/aA induction on memory formation and, in particular, on T cell exhaustion using models of viral infection and anti-tumor immunity. In parallel to phenotypic and functional analyses, we will also employ state-of-the-art technologies, such as transcriptomics and metabolomics, to define the impact of E2 on T cell differentiation and function at the physiological, cellular and molecular level.Our experiments will provide a comprehensive view how E2 and the induction of NFATc1/aA induction controls T cell-mediated immune responses during persistent infections and cancerogenesis. The results of this project are not only addressing fundamental molecular questions of adaptive immune responses but will also pave the way to develop advanced T cell-mediated immunotherapies against cancer.