T cell regulation of pathogenic B cell in systemic autoimmunity

系统性红斑狼疮（SLE，lupus）的特点是产生致病性自身抗体 促进组织损伤，包括肾脏狼疮中的致病性自身抗体经历亲和力 次级淋巴细胞内生殖中心（GC）的成熟和免疫球蛋白（Ig）同种型转换 器官（SLO），是co 4· T细胞依赖性（TD）B细胞成熟的位点。然而，效应子的特定子集 促进自身反应性B发育的co 4· T细胞以及这些细胞的调节尚未明确。 滤泡性辅助性T细胞（Tfh）包括一个亚群的co 4· T辅助性（Th）细胞，其表型和功能 与其它Th细胞不同，如经典的Th 1、Th 2和Th 17亚群。我用模型系统 探讨Tfh细胞因子的产生及其在B细胞成熟中的作用，长期目标是研究 这些事件在SLE中致病性自身抗体的产生中起作用。我们发现转录因子的表达 T-bet是Tfh和Th 1细胞扩增和IFN-γ产生以及病毒特异性GC输出所必需的。激活 STAT 4与IL-21一起沿着促进Tfh细胞中的T-bet表达，如在Th 1细胞中一样。STAT 4和T-bet表达 由IL-12和IFN-β驱动。转录调节Tfh细胞扩增和共同生产所需的 IL-21和IFN-γ，以在1型免疫应答时实现适当的GC应答。类似于viral 感染Tfh和Th 1细胞在鼠和人狼疮中扩增并持续存在，具有相似的STAT 4和 T-bet表达，以及IFN-γ和IL-21的共表达。然而，尽管它们能共同产生IFN-γ， IL-21、Tfh而不是Th 1细胞在鼠狼疮中会随着时间的推移而抑制T-bel的表达， 来自狼疮患者的人cTfh细胞。我们假设狼疮的慢性炎症环境改变了 效应Th细胞的遗传表达导致致病性B细胞的异常调节， 疾病因此，我们将探讨在功能上影响致病性的遗传调控的时间变化， 与急性1型病毒感染相比，自身免疫性疾病中Tfh细胞和GC B细胞的发育我们将 联合收割机细胞技术与新的基因组方法研究染色质结构影响 功能性基因表达，然后在一个并排的控制顺式调控元件的鉴定 这些T和B细胞的比较随着疾病的进展。这将使我们能够探索时间的相互作用， 转录调控，动态染色质结构和基因组组织的调控， 致病性T和B细胞。使用细胞技术，我们还将研究发育的要求， 表达T-bet的炎性B细胞亚群。我们将确定细胞因子和T细胞， 这些自身抗体分泌B细胞的起源。最终，这项工作应该有助于区分致病性 和非致病性效应T细胞，有助于治疗设计的新途径。

Systemic lupus erythematosus (SLE, lupus) is characterized by the generation of pathogenic autoantibodies that promote tissue injury, including in the kidney. Pathogenic autoantibodies in lupus undergo affinity maturation and immunoglobulin (lg) isotype switching in germinal centers (GCs) within secondary lymphoid organs (SLOs), a site of co4• T cell-dependent (TD) B cell maturation. Yet, the specific subsets of effector co4• T cells that promote autoreactive B development, and the regulation of these cells, are not well defined. T follicular helper (Tfh) cells comprise a subset of co4• T helper (Th) cells, phenotypically and functionally distinct from other Th cells, such as the classical the Th 1, Th2 and Th17 subsets. I have used model systems to explore Tfh-cell cytokine production and its role in B cell maturation, with the long-term goal to investigate these events in pathogenic autoantibody production in SLE. We show that expression of the transcription factor T-bet is required for Tfh and Th1 cell expansion and IFN-γ production, and viral-specific GC output. Activated STAT4 promotes T-bet expression in Tfh cells, as in Th1 cells, along with IL-21. STAT4 and T-bet expression is driven by IL-12 and IFN-β. which are needed to transcriptionally regulate Tfh cell expansion and coproduction of IL-21 and IFN-γ, to enable a proper GC response upon type 1 immune response. Similar to viral infection Tfh and Th1 cells expand and persist in murine and human lupus, with similar patterns of STAT4 and T-bet expression, alongside co-expression of IFN-y and I L-21. Yet, despite their robust co-production of IFN-γ and IL-21, Tfh and not Th1 cells in murine lupus extinguish T-bel expression over lime, with its absence also in human cTfh cells from lupus patients. We hypothesize that the chronic inflammatory milieu of lupus alters the genetic expression of effector Th cells leading to aberrant regulation of pathogenic B cells that contribute to disease. Accordingly, we will explore temporal changes in genetic regulation that functionally impact pathognic Tfh cell and GC B cell developemnt in autoimmune disease compared to an acute type 1 viral infection. We will combine cellular techniques with novel genomic approaches to investigate chromatin architecture influencing functional gene expression, followed by identification of the controlling cis-regulatory elements in a side by side comparison of these T and B cells as disease progresses. This will allow us to explore the temproal interplay of transcriptional regulation, dynamic chromatin architecture and genomic organization in the regulation of pathogenic T and B cells. Using cellular techniques, we will also examine the developmental requirements for the T-bet expressing inflammatory B cell subset. We will determine the cytokines and the T cells that promote the genesis of these autoantibody secreting B cells. Ultimately, this work should help distinguish pathogenic and nonpathogenic effector T cells, aiding new avenues of therapeutic design.