The role of the transcription factor c-Maf in controlling mucosal inflammation in the intestine

肠道免疫系统不断暴露于无数无害和致病的微生物。因此，同时提供保护性免疫和免疫耐受性代表了对粘膜免疫系统的独特挑战。CD 4 + T细胞协调肠道免疫应答，失调的T细胞应答导致慢性炎症性肠病（IBD）。白细胞介素-10在T细胞介导的肠道免疫调节中起着重要作用。它可以由调节性T细胞（TCFs）以及促炎性T细胞产生，作为一种有效的自限机制。因此，通过肠T细胞产生IL-10的治疗性操作代表了在IBD患者中重建生理耐受性的有吸引力的机会。然而，各种T细胞亚型对IL-10产生的调节仍然没有完全了解。我们以前已经确定了转录因子Blimp-1和c-Maf作为促炎性Th 1细胞产生IL-10的中心调节因子。我们的初步数据现在确定c-Maf作为一个独特的转录因子参与肠道调节T细胞介导的炎症反应在多个水平。C-Maf主要由肠道调节性（Treg）和常规CD 4 + T细胞亚群表达，并与IL-10产生相关。T细胞特异性c-Maf敲除几乎消除了所有T细胞亚群的IL-10产生，并导致Foxp 3-和Foxp 3 + T细胞的炎性细胞因子IL-17和IFN-γ的表达增加。有趣的是，c-Maf敲除小鼠在肠中也完全缺乏ROR γ mat + Treg亚群，最近已鉴定其由肠组织中的微生物群诱导。因此，c-Maf似乎在调节肠道T细胞稳态和免疫方面发挥广泛而非冗余的作用。本研究拟进一步阐明c-Maf对肠道CD 4 + T细胞表型和功能的作用，并试图确定c-Maf表达的调控信号和机制。我们还将讨论c-Maf促进不同肠道CD 4 + T细胞亚群中免疫调节表型的转录特征和分子机制。T细胞和Foxp 3特异性c-Maf ko小鼠将用于确定c-Maf在确定的肠道炎症体内模型中对促炎性和调节性T细胞的作用。此外，我们将采用我们最近开发的抗原反应性T细胞富集（ARTE）技术来表征人CD 4 + T细胞亚群中的c-Maf表达和功能，该技术允许分离和表征对来自血液和肠组织的肠抗原具有特异性的人炎性和调节性T细胞。我们建议，我们的项目将有助于确定小鼠和人类肠道T细胞稳态和耐受性的中央调节因子，这将揭示IBD特异性治疗干预的新可能性。

The intestinal immune system is constantly exposed to myriads of harmless and pathogenic microbes. Thus providing protective immunity and immunological tolerance at the same time represents a unique challenge for the mucosal immune system. CD4+ T cells orchestrate intestinal immune responses and deregulated T cell responses contribute to chronic inflammatory bowel disease (IBD). Interleukin-10 plays a central role for T cell-mediated intestinal immune regulation. It can be produced by regulatory T cells (Tregs) as well as by pro-inflammatory T cells as a potent self-limiting mechanism. Thus, therapeutic manipulation of IL-10 production by intestinal T cells represents an attractive opportunity to re-establish physiological tolerance in IBD patients. However, the regulation of IL-10 production by the various T cell subtypes is still not fully understood. We have previously identified the transcription factors Blimp-1 and c-Maf as central regulators of IL-10 production by pro-inflammatory Th1 cells. Our preliminary data now identify c-Maf as a unique transcription factor involved in intestinal regulation of T cell-mediated inflammatory responses at multiple levels. C-Maf is mainly expressed by intestinal regulatory (Treg) and conventional CD4+ T cell subsets and correlates with IL-10 production. T cell-specific c-Maf knockout almost abolished IL-10 production by all T cell subsets and led to increased expression of the inflammatory cytokines IL-17 and IFN-gamma by Foxp3- and Foxp3+ T cells. Interestingly c-Maf knockout mice also completely lack the RORgammat+ Treg subset in the intestine, which has recently been identified to be induced by microbiota in intestinal tissues. Thus c-Maf seems to play a broad and non-redundant role for the regulation of intestinal T cell homeostasis and immunity. Here we propose to further elucidate the role of c-Maf for the phenotype and function of intestinal CD4+ T cells and try to identify the signals and mechanisms regulating c-Maf expression. We will also address the transcriptional signature and the molecular mechanisms by which c-Maf promotes the immune-regulatory phenotype in different intestinal CD4+ T cell subsets. T cell- and Foxp3-specific c-Maf ko mice will be used to determine the role of c-Maf for pro-inflammatory and regulatory T cells in defined in vivo models of intestinal inflammation. In addition we will characterize c-Maf expression and function in human CD4+ T cell subsets employing our recently developed Antigen-Reactive-T cell Enrichment (ARTE)-technology allowing to isolate and characterize human inflammatory and regulatory T cells specific for intestinal antigens derived from blood and intestinal tissues. We propose that our project will help to define a central regulator of intestinal T cell homeostasis and tolerance in mouse and man, which will reveal new possibilities for specific therapeutic intervention in IBD.