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

NFAT 在 Tcon 和 Treg 的发育和功能中的总体作用

• 批准号: 456615866
• 负责人: Professorin Dr. Friederike Berberich-Siebelt
• 金额: --
• 依托单位: Pathologisches Institut
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/456615866?language=en
• 关键词: overall; role; NFAT; development; function

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.

在 T 淋巴细胞中，激活，即活化 T 细胞核因子 (NFAT) 的核转位主要取决于 T 细胞受体 (TCR) 和伴随的钙信号。换句话说，NFAT 主要翻译抗原特异性、亲和力和亲和力。 TCR.NFAT 由一系列转录因子组成，其中淋巴细胞表达钙调节的 NFATc1、NFATc2 和 NFATc3。个体成员的双缺陷小鼠揭示了许多关于其在常规（Tcon）和调节（Treg）T细胞中的特定功能的见解。此外，小鼠中钙信号的消除或改变暗示了NFAT的整体作用，但永远无法精确区分。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，分别在 αβ Tcon 和 Foxp3+ Tregs 中完全缺乏 NFAT 蛋白。第一个后代发现了严重受影响的小鼠，体型较小且过早死亡。令我们最初惊讶的是，TKO.Cd4cre 和 TKO.FIC 均患有淋巴结病、脾肿大伴嗜酸性粒细胞增多和在 TKO.Cd4cre 中，胸腺选择似乎发生了改变，导致胸腺和外周出现异常的亚群，但在 TKO.FIC 小鼠中几乎没有任何 Tregs 发育到正常数量，我们发现。为了使完全缺乏 NFAT 的 Treg 无法发挥所有效应功能，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。总之，这些知识还应该支持针对 T 细胞受体及其信号转导的治疗操作的设计。