A T cell STAT3-BATF axis regulates intestinal gamma delta T cell homeostasis and disease

项目总结。肠道免疫反应失调是炎症性肠病的标志 疾病(IBD)，但目前针对这些反应的治疗方法往往显示出较差的长期疗效。这个 疗效不佳的原因可能是对免疫学和微生物学的不完全了解。 导致疾病的相互作用。最近对人类IBD患者免疫相互作用的研究已经 强调免疫调节性T细胞和炎性T细胞之间的失调相互作用是 疾病。然而，涉及的确切细胞参与者以及这些失调的相互作用是如何发生的仍然存在。 不清楚。在努力弥合这些知识差距的过程中，我们的长期目标是界定 管理免疫调节T细胞和炎症T细胞之间的相互作用以及这些相互作用如何 旨在改进IBD的治疗方法。 在我们的初步数据中，我们发现携带常规T细胞(即αβT细胞受体+)特异性的小鼠 STAT3和BATF缺失会发展成类似于肠道的侵袭性自发性结肠炎 炎症是人类IBD的特征。有趣的是，已知的疾病中介物和抑制者 (产生IL-17的Th17和Foxp3+T调节(Treg)细胞)，等同于STAT3/BATF-双缺陷 小鼠和无疾病的STAT3和BATF单缺陷小鼠。这些数据表明，a STAT3/BATF- 受调控的转录程序诱导Th17/Treg非依赖的免疫调节功能 维持肠道内环境平衡。常规T细胞STAT3/BATF缺陷小鼠的肠道疾病 以依赖微生物区系的炎性γδT细胞快速积累为特点，类似于在 IBD患者的病变结肠组织。这些数据表明，表达STAT3/BATF的常规T细胞 与微生物区系和γδT细胞相互作用以抑制疾病。这项研究的目标是确定如何 STAT3和BATF调节常规免疫调节T细胞的相互作用和功能，并 定义依赖微生物区系的γδT细胞如何导致疾病。这里我们假设传统的T细胞 STAT3和BATF共同调节影响与微生物区系相互作用的基因网络，并 炎症性肠病的致病γδT细胞反应。我们将通过两个目标来检验这一假设：1)定义 STAT3/BATF调节的转录网络在炎症性肠病中控制传统的γδT细胞相互作用和2) 确定微生物区系诱导的γδT细胞在推动炎症性肠病中的作用。这项工作的成果将是 因为我们已经确定了一种传统T细胞维持的新机制，这具有重大意义和创新性 并开发了一种新的小鼠模型来研究这些细胞与细胞的相互作用 微生物区系和γδT细胞与疾病此外，我们的研究将为可能起作用的新疗法提供洞察力 支持STAT3/BATF+常规T细胞，预防IBD的发生。

PROJECT SUMMARY. A dysregulated intestinal immune response is a hallmark of inflammatory bowel disease (IBD), but current therapies that target these responses often exhibit poor long-term efficacy. The reasons for this poor efficacy likely stem from an incomplete understanding of the immunological and microbial interactions that lead to disease. Recent studies examining immune interactions in human IBD patients have highlighted dysregulated interactions between immunoregulatory and inflammatory T cells as a key feature of disease. However, the exact cellular players involved and how these dysregulated interactions occur remain unclear. In efforts to close these gaps in knowledge, our long-term goals are to define the mechanisms that govern the interactions between immunoregulatory and inflammatory T cells and how these interactions can be targeted to improve IBD therapeutics. In our preliminary data, we show that mice carrying conventional T cell (i.e. αβ T cell receptor+)-specific deletions of STAT3 and BATF develop an aggressive spontaneous colitis that closely resembles intestinal inflammation that is characteristic of human IBD. Intriguingly, the known mediators and suppressors of disease (IL-17-producing Th17 and Foxp3+ T regulatory (Treg) cells), are equivalent in STAT3/BATF-double deficient mice and disease-free STAT3 and BATF-single deficient mice. These data suggest that a STAT3/BATF- regulated transcriptional program induces Th17/Treg-independent immunoregulatory function that is critical for maintaining intestinal homeostasis. Intestinal disease in conventional T cell STAT3/BATF-deficient mice was marked by the rapid accumulation of microbiota-dependent inflammatory γδ T cells, resembling those found in lesional colonic tissues of IBD patients. These data suggest that STAT3/BATF-expressing conventional T cells interact with the microbiota and γδ T cells to suppress disease. The objective of this study is to determine how STAT3 and BATF regulate the interactions and functions of conventional immunoregulatory T cells and to define how microbiota-dependent γδ T cells contribute to disease. Here we hypothesize that conventional T cell STAT3 and BATF cooperatively regulate a gene network that influences interactions with the microbiota and pathogenic γδ T cell responses in IBD. We will test this hypothesis via two aims in which we will 1) define the STAT3/BATF-regulated transcriptional network that governs conventional-γδ T cell interactions in IBD and 2) determine the role the microbiota-induced γδ T cells in driving IBD. The results of this work will be highly significant and innovative as we have identified a novel mechanism by which conventional T cells maintain intestinal homeostasis and developed a new murine model to examine interactions of these cells with the microbiota and γδ T cells in disease. Further, our studies will provide insight into new therapies that may act to bolster STAT3/BATF+ conventional T cells to prevent the onset of IBD.