Regulation of Tfh function in autoimmunity by TSLP

项目摘要 生发中心(GCs)是在次级淋巴中扩展的动态免疫微结构 感染或免疫期间的器官。GCS也可在缺乏显性免疫或 可检测到的外来感染(称为自发性GC，SPT-GC)。而不是诱导GC形成 在免疫或抗病原体反应期间，SPT-GC对内源性抗原和 这在一定程度上导致了慢性自身免疫力。SPT-GC增大，在自身免疫倾向的小鼠中更常见 在没有可检测到的病原体或公开的免疫挑战的情况下。SPT-GC与 狼疮易感小鼠的核反应性自身抗体滴度以及从SPT-GC分离的许多GC B细胞的形成 易患系统性红斑狼疮的小鼠是自身反应性的。SPT-GC内的TFH细胞和CGC B细胞在 调节高亲和力自身抗体的产生。 SPT-GC在几种不同的自身免疫性疾病患者中也被检测到，包括 系统性红斑狼疮(SLE)、类风湿关节炎(RA)、多发性硬化(MS)、干燥综合征 (SS)和1型糖尿病(T1D)。例如，儿童系统性红斑狼疮患者的循环前血小板数量增加。 GC B细胞和成人SLE患者循环中的Tfh细胞增多。这些数据表明了重要的作用 SPT-GCs在致病性自身抗体的产生中起作用。 虽然SPT-GC与自身免疫的相关性是明确的，但控制其发展的因素 仍然默默无闻。我们发现细胞因子胸腺间质淋巴生成素(TSLP)起着重要作用 在小组委员会-GC的发展中。TSLP和TSLPR缺陷小鼠的SPT数量显著减少。 GCS，而那些现存的似乎是残留的。与此观察一致的是，我们还发现TSLP 信号转导对Tfh的分化至关重要。作为一个整体，这些数据表明了 TSLP在SPT和诱导型GC形成和功能中的作用。我们将通过确定下列因素的作用来检验这一假设 TSLP在Tfh的发育和功能中的作用(目标1)，并确定Tfh特异的TSLP信号在 有自身免疫倾向的小鼠。

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.