Tfh细胞释放核酸降解酶DNASE1L3在维持生发中心“免疫自稳”中的作用和机制研究

滤泡辅助性T（Tfh）细胞的多样性在维持生发中心（GC）“免疫自稳”中起关键作用，其功能异常伴随着GC反应失衡，与多种自身免疫病甚至肿瘤的发生发展密切相关。90%低亲和力的B细胞在GC进行分化时会凋亡，释放大量的核酸和DNA等核抗原（NA）。研究表明，NA能促进抗核抗体的形成，进而诱发自身免疫病如系统性红斑狼疮（SLE）。目前尚不清楚GC中不断产生的NA如何被清除？脱氧核糖核酸酶-γ（DNASE1L3）作为外周血中降解NA的关键酶，其全身性缺失小鼠会自发SLE。我们首次发现一群高表达DNASE1L3的Tfh细胞亚群，而在小鼠Tfh细胞中特异性敲除后能引起典型的SLE症状。因此，我们将结合基因改造小鼠，单细胞和BCR测序等方法，深入研究：1、DNASE1L3+Tfh细胞亚群的生物学功能及其在GC“免疫自稳”中的作用及其机制；2、Tfh细胞缺失Dnase1l3后在SLE发生发展中的作用及机制。

The diversity of T follicular helper (Tfh) cells plays a key role in maintaining the "immune homeostasis" in the germinal center (GC) response. Abnormal function of Tfh cells is accompanied by unbalanced GC response, which is closely related to the occurrence and development of a variety of autoimmune diseases and even tumors. During the differentiation of B cells in GC response, 90% of low-affinity B cells will undergo apoptosis, releasing large amounts of nuclear antigens (NA) such as nucleic acid substances and DNA. Studies have shown that NA can promote the formation of anti-nuclear antibodies and then induce autoimmunity such as systemic lupus erythematosus (SLE). It is unclear how the NA continuously generated in the GC response is degraded? Deoxyribonuclease-γ (DNASE1L3) is the key enzyme to degrade NA in peripheral blood, its systemic deletion in mice will spontaneously induce SLE. For the first time, we found a group of Tfh cells that express DNASE1L3. The specific knockout of Dnase1l3 in mouse Tfh cells can cause typical SLE symptoms. Therefore, we will combine genetically modified mice, single cell and BCR sequencing and other methods to conduct in-depth research: 1. The biological functions of the DNASE1L3+Tfh subgroup and its role and mechanism in maintaining the "immune homeostasis" of the germinal center; 2. The role and mechanism of Tfh cells lacking Dnase1l3 in the occurrence and development of SLE.