The overall role of NFAT in development and function of Tcon and Treg

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In T lymphocytes, activation, i.e. nuclear translocation of Nuclear factor of activated T-cells (NFAT) depends mostly on T-cell receptor (TCR) and concomitant calcium signals. In other words, NFAT dominantly translates antigen specificity, affinity and avidity of the TCR. NFAT consists of a family of transcription factors, of which lymphocytes express calcium-regulated NFATc1, NFATc2 and NFATc3. Until now, single or double-deficient mice for individual members exposed many insights into their specific function in conventional (Tcon) and regulatory (Treg) T cells. In addition, abrogated or altered calcium signals in mice hinted towards the overall role of NFAT, but could never distinguish precisely between NFAT and other calcium-regulated events. Therefore, we propose to analyze Nfatc1fl/fl.Nfatc2―/―.Nfatc3fl/fl.Cd4cre (TKO.Cd4cre) and Nfatc1fl/fl.Nfatc2―/―.Nfatc3fl/fl.FIC (TKO.FIC) mice, being totally devoid of NFAT proteins in αβ Tcon and in Foxp3+ Tregs, respectively.First offspring uncovered severely affected mice, being smaller and expiring prematurely. To our initial surprise, both TKO.Cd4cre and TKO.FIC suffered from lymphadenopathy, splenomegaly with eosinophilia and inflammation of multiple other organs. In TKO.Cd4cre it seems that thymic selection is altered, leading to unusual sub-populations in thymus and periphery, but hardly any Tregs. In TKO.FIC mice, however, Tregs develop to normal numbers and we have to hypothesize that totally NFAT-deficient Tregs cannot exert all effector functions. With the proposed experiments, we hope to describe the respective phenotype in detail to understand the overall role of NFAT in Tcon and Treg. After all, such knowledge should also support the design of therapeutical manipulations addressing the T-cell receptor and its signal transduction.