Regulation of Tfh function in autoimmunity by TSLP

项目摘要 生发中心（GC）是动态免疫微结构，在次级淋巴细胞中扩增， 在感染或免疫过程中。GC也可以在没有明显免疫的情况下发展， 可检测的外源性感染（称为自发性GC，Spt-GC）。而不是诱导性GC 在免疫或抗病原体应答期间，Spt-GC响应内源性抗原而产生， 在一定程度上导致慢性自身免疫。Spt-GCs在自身免疫易感小鼠中增大且更常见 在没有可检测的病原体或明显的免疫攻击的情况下。Spt-GC表现出线性相关性， 在狼疮易感小鼠和从Spt-GC分离的许多GC B细胞中，出现了核反应性自身抗体滴度 是自身反应性的。Spt-GCs内的Tfh细胞和CGC B细胞两者在以下方面起重要作用： 调节高亲和力自身抗体的产生。 Spt-GCs也在几种不同的自身免疫性疾病患者中检测到， 系统性红斑狼疮（SLE）、风湿性关节炎（RA）、多发性硬化（MS）、干燥综合征 (SS)1型糖尿病（T1 D）例如，儿童SLE患者的循环前- GC B细胞和成人SLE患者表现出增加的循环Tfh细胞。这些数据表明， Spt-GCs在致病性自身抗体产生中的作用。 虽然Spt-GCs与自身免疫的相关性是明确的，但控制其发展的因素 保持模糊。我们已经发现细胞因子胸腺基质淋巴细胞生成素（TSLP）起着重要作用， Spt-GCs的发展。TSLP和TSLPR缺陷小鼠的Spt- GC，那些存在的似乎是残留的。与这一观察一致，我们还发现TSLP 信号传导对于Tfh的分化至关重要。总的来说，这些数据表明， TSLP在Spt和诱导的GC形成和功能中的作用我们将通过确定以下因素的作用来检验这一假设： TSLP在Tfh发育和功能中的作用（目的1），并确定Tfh特异性TSLP信号转导在Tfh发育和功能中的作用。 自身免疫易感小鼠

Project Summary Germinal centers (GCs) are dynamic immune microarchitectures that expand in secondary lymphoid organs during infection or immunization. GCs can also develop in the absence of overt immunization or detectable adventitious infection (called spontaneous GCs, Spt-GCs). As opposed to induced GCs that form during immunization or anti-pathogen responses, Spt-GCs develop in response to endogenous antigens and contribute, in part, to chronic autoimmunity. Spt-GCs are enlarged and more frequent in autoimmune-prone mice in the absence of detectable pathogens or overt immune challenge. Spt-GCs exhibit a linear correlation with nuclear-reactive autoantibody titers in lupus-prone mice and many GC B cells isolated from Spt-GCs developed in SLE-prone mice are autoreactive. Both Tfh cells and CGC B cells within the Spt-GCs play essential roles in regulating high-affinity autoantibody production. Spt-GCs have also been detected in patients with several different autoimmune diseases including Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA), Multiple Sclerosis (MS), Sjogren’s syndrome (SS) and Type 1 diabetes (T1D). For example, pediatric SLE patients have elevated numbers of circulating pre- GC B cells and adult SLE patients exhibit increased circulating Tfh cells. These data indicate the important roles that Spt-GCs play in pathogenic autoantibody production. While the correlation of Spt-GCs with autoimmunity is clear, the factors that control their development remain obscure. We have found that the cytokine thymic stromal lymphopoietin (TSLP) plays a significant role in the development of Spt-GCs. TSLP- and TSLPR-deficient mice have dramatically reduced numbers of Spt- GCs, and those that exist appear to be vestigial. Consistent with this observation, we have also found that TSLP signaling is critical for the differentiation of Tfh. Taken as a whole, these data demonstrate an important role for TSLP in Spt- and induced-GC formation and function. We will test this hypothesis by determining the role of TSLP in Tfh development and function (Aim 1), and determine the role of Tfh-specific TSLP signaling in autoimmune prone mice.