Mechanisms of homeostatic peripheral T cell maintenance in the absence of the epigenetic regulator SETD1A.

T细胞对于对病原体和肿瘤抗原产生有效反应的免疫能力具有重要作用。为此，外周T细胞池的多样性和大小对免疫反应的激发、强度和寿命至关重要。在整个衰老过程中，T细胞的从头产生减少，将维持外周T细胞数量的动态平衡机制置于焦点。在其他特征中，衰老和DNA损伤是衰老的标志，表观遗传调节因子SETD1A分别在体外癌细胞和体内造血祖细胞中保护两者。我们已经确定SETD1A是小鼠造血干细胞和祖细胞中的关键组蛋白甲基转移酶，它控制着几乎所有DNA损伤识别和修复途径的成分的表达。利用T细胞特异性Cre重组酶缺失小鼠(CD4-Cre)，我们提供了初步数据，指出SETD1A在维持外周T细胞库中的作用。胸腺内T细胞分化的晚期不受影响，因此，SETD1A在外周T细胞中是至关重要的。在这项建议中，我们概述了旨在揭示SETD1A控制外周T细胞池大小的机制的实验，并探索SETD1A在年龄相关表型(包括免疫衰老和淋巴肿大)中的功能。

T cells are of great importance for immune competence conferring efficient responses against pathogens and tumor antigens. To this end diversity and size of the peripheral T cell pool is crucial for the instigation, intensity, and longevity of immune responses. Throughout the aging process, de novo production of T cells decreases, placing homeostatic mechanisms maintaining peripheral T cell numbers into the focus. Among other features, senescence and DNA damage are hallmarks of aging, and the epigenetic regulator SETD1A protects from either in cancer cells in vitro and in hematopoietic progenitor cells in vivo, respectively. We have identified SETD1A as the key histone methyltransferase in hematopoietic stem and progenitor cells in mice that controls the expression of components of virtually all DNA damage recognition and repair pathways. Using T cell specific CRE-recombinase deleter mice (CD4-Cre), we present here preliminary data pointing at a role for Setd1a in the maintenance of the peripheral T cell pool. Late stages of intrathymic T cell differentiation are not affected, thus, Setd1a is crucial specifically in peripheral T cells. Within this proposal we outline experiments aiming at uncovering mechanisms by which Setd1a controls the peripheral T cell pool size and explore the function of Setd1a in the context of age-associated phenotypes including immune senescence and lymphomagenesis.