Mechanisms Controlling the Development and Function of Intestinal Effector Treg cells

控制肠道效应 Treg 细胞发育和功能的机制

基本信息

批准号：
10658359
负责人：
ROBIN D HATTON
金额：
$ 72.97万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-21 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10658359
关键词：
Amplifiers Autoantigens Biological Biology CD4 Positive T Lymphocytes Calibration Cell Differentiation process Cell Maintenance Cells Chemosensitization Clinical Trials Clinical Trials Design Colitis Competence Development Disease Environment Equilibrium Eragrostis FOXP3 gene Fibrosis GATA3 gene Gene Expression Gene Targeting Generations Genes Genetic study Homeostasis Human Human Genetics IL10RB gene IL17 gene IL2 Signaling Pathway Immune Immune system Immunity Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Interleukin 2 Receptor Interleukin-10 Interleukin-2 Intervention Intestines Large Intestine Lesion Maintenance Mediating Methods Mus Mutation Myeloid Cells Output Pathogenesis Pathogenicity Pathologic Pathway interactions Patients Peripheral Play Population Production Receptor Signaling Regulation Regulatory T-Lymphocyte Role STAT3 gene Signal Pathway Signal Transduction Source Stat5 protein T-Lymphocyte TNF gene TNFSF15 gene Testing Therapeutic Thymus Gland Tissues Transcriptional Regulation Tumor Necrosis Factor Receptor commensal microbes cytokine disorder risk early onset effector T cell food antigen gut inflammation gut microbiota immunoregulation interleukin-10 receptor knock-down man member microbiota mouse model novel novel strategies novel therapeutic intervention pleiotropism programs response restraint synergism therapeutic target transcription factor

项目摘要

PROJECT SUMMARY Mechanisms Controlling the Development and Function of Intestinal Effector Treg Cells. The pathogenesis of a spectrum of disorders referred to as inflammatory bowel disease (IBD) is characterized by immune dysregulation to components of the enteric microbiota. Findings from mouse and man highlight a critical, non-redundant role for the immunoregulatory cytokine IL-10 in maintenance of intestinal immune homeostasis. Our labs have shown that Foxp3+ regulatory T (Treg) cells are, overwhelmingly, the major source of IL-10 in the intestines, where many of these cells co-express the canonical “Th17” transcription factor, RORt—particularly in large intestine (LI). However, IL-10 is only produced by a subset of Treg cells—defined as ‘effector’ (e)Treg cells. Mechanisms that control the development of eTreg cells are incompletely understood. The premise of this application, founded on recent discoveries from, and synergy between, the two PIs (Weaver, Hatton) is that heretofore unappreciated interplay between signaling pathways of the IL-2 and TNF superfamilies has a central role in regulating the development and function of eTreg cells in the intestines. Specifically, we have identified the TNF receptor superfamily signaling pair, TNFSF15-TNFRSF25 (TL1A-DR3), as an important amplifier of the transition of “central” (c)Treg cells into eTreg cells and propose that this pathway plays an important role in calibrating IL-2–driven control of the Treg cell program via multiple mechanisms. We hypothesize that the TL1A- DR3 pathway is non-redundant in its regulation of IL-2 receptor (IL-2R) signaling to modulate the size and cTreg– eTreg balance of the LI Treg cell pool both at homeostasis and under inflammatory conditions. Further, we posit that DR3 acts through multiple mechanisms to alter output of the IL-2R to regulate development of IL-10– producing eTreg cells. We propose that a major driver of eTreg cell development is increased STAT3 output of the IL-2R, which is enhanced by actions of DR3 to: (i) increase sensitivity of the IL-2R; and (ii) decrease pSTAT3 degradation, thereby altering the IL-2–induced STAT5/STAT3 ratio. Finally, we propose that other TNFRSF members contribute to eTreg cell maintenance after DR3 expression declines. We test this hypothesis through complementary, but not inter-dependent, Aims, leveraging: a novel method for generating stable, colitis-curing Treg cells ex vivo; new approaches for efficient gene knock-downs in primary T cells; and new gene-targeted mouse models to define mechanisms governing the convergence of these signaling pathways in controlling the transcriptional regulation of Il10 and the eTreg program. Successful completion of these Aims will establish new biological paradigms and inform novel therapeutic approaches by which endogenous IL-10 can be up-regulated and the differentiation and function of eTreg cells enhanced to treat human IBD.

项目概要控制肠道效应 Treg 细胞发育和功能的机制。炎症性肠病 (IBD) 等一系列疾病的发病机制具有以下特征：小鼠和人类的研究结果强调了肠道微生物群成分的免疫失调。免疫调节细胞因子 IL-10 在维持肠道免疫稳态中的非冗余作用。我们的实验室表明，Foxp3+ 调节性 T (Treg) 细胞绝大多数是 IL-10 的主要来源。肠道，其中许多细胞共同表达典型的“Th17”转录因子 RORt，尤其是然而，IL-10 仅由 Treg 细胞的一个子集（定义为“效应细胞”(e)Treg）产生。控制 eTreg 细胞发育的机制尚不完全清楚。该应用程序建立在两个 PI（Weaver、Hatton）的最新发现和协同作用的基础上：迄今为止，IL-2 和 TNF 超家族信号通路之间的相互作用尚未得到充分认识，这一相互作用具有重要的意义。具体来说，我们已经确定了 eTreg 细胞在调节肠道发育和功能中的作用。 TNF 受体超家族信号对 TNFSF15-TNFRSF25 (TL1A-DR3)，作为重要的放大器 “中央”(c)Treg 细胞向 eTreg 细胞的转变，并提出该途径在通过多种机制校准 IL-2 驱动的 Treg 细胞程序控制。 DR3 通路在调节 IL-2 受体 (IL-2R) 信号传导以调节大小和 cTreg 方面是非冗余的 LI Treg 细胞池在稳态和炎症条件下的 eTreg 平衡进一步，我们假设。 DR3 通过多种机制发挥作用，改变 IL-2R 的输出，从而调节 IL-10 的发育—— 我们认为 eTreg 细胞发育的主要驱动力是 STAT3 输出的增加。 IL-2R，通过 DR3 的作用增强：(i) 增加 IL-2R 的敏感性；(ii) 降低 pSTAT3；降解，从而改变 IL-2 诱导的 STAT5/STAT3 比率最后，我们提出其他 TNFRSF。 DR3 表达下降后，成员有助于 eTreg 细胞的维持。互补但不相互依赖，目标，利用：一种产生稳定性、结肠炎治疗的新方法离体 Treg 细胞；原代 T 细胞中有效基因敲除的新方法和新的基因靶向；小鼠模型来定义控制这些信号通路收敛的机制 Il10 的转录调控和 eTreg 计划的成功完成将建立新的目标。生物学范例并为新的治疗方法提供信息，通过这些方法可以上调内源性 IL-10 增强 eTreg 细胞的分化和功能以治疗人类 IBD。