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

在T淋巴细胞中，活化，即活化T细胞核因子（NFAT）的核易位主要依赖于T细胞受体（TCR）和伴随的钙信号。换句话说，NFAT主要翻译TCR的抗原特异性、亲和力和亲和性。NFAT由一系列转录因子组成，其中淋巴细胞表达钙调控的NFATc1、NFATc2和NFATc3。到目前为止，单个成员的单缺陷或双缺陷小鼠揭示了它们在常规（Tcon）和调节性（Treg） T细胞中的特定功能。此外，小鼠中钙信号的消失或改变暗示了NFAT的整体作用，但无法准确区分NFAT和其他钙调节事件。因此，我们建议分析Nfatc1fl/fl. nfatc2 - / - . nfatc3fl /fl。Cd4cre （TKO.Cd4cre）和Nfatc1fl/fl. nfatc2 - / - . nfatc3fl /fl。FIC （TKO.FIC）小鼠，αβ Tcon和Foxp3+ Tregs中分别完全缺乏NFAT蛋白。第一个后代发现了受到严重影响的老鼠，它们体型更小，而且过早死亡。出乎我们意料的是，两人都被TKO了。Cd4cre和TKO。FIC表现为淋巴结病变、脾肿大伴嗜酸性粒细胞增多及其他多脏器炎症。TKO。Cd4cre似乎改变了胸腺选择，导致胸腺和周围的不寻常亚群，但几乎没有treg。TKO。然而，FIC小鼠的treg发育到正常数量，我们不得不假设完全缺乏nfat的treg不能发挥所有的效应功能。通过提出的实验，我们希望详细描述各自的表型，以了解NFAT在Tcon和Treg中的整体作用。毕竟，这些知识也应该支持针对t细胞受体及其信号转导的治疗操作的设计。

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.