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

• 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
• 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

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.

项目摘要 控制肠道效应treg细胞的发育和功能的机制。这 称为炎症性肠病（IBD）的一系列疾病的发病机理的特征是 免疫失调对肠菌群的成分。鼠标和人的发现突出显示了一个关键 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，其中许多细胞共表达了规范的“ Th17”转录因子Rort-尤其是 在大肠（LI）中。但是，IL-10仅由Treg细胞的子集产生 - 定义为“效应器”（E）Treg 细胞。控制ETREG细胞开发的机制尚不完全理解。这个前提 应用于两个PI（Weaver，Hatton）的最新发现和协同作用的应用程序是 迄今未欣赏IL-2和TNF超家族的信号通路之间的不受影响的相互作用具有中央 在调节肠中ETREG细胞的发育和功能中的作用。具体来说，我们已经确定了 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细胞转变为ETREG细胞，并提出该途径在 通过多种机制校准对Treg细胞程序的IL-2驱动控制。我们假设TL1A- DR3途径在调节IL-2受体（IL-2R）信号传导的调节时不冗余以调节大小和CTREG – 在体内稳态和炎症条件下，Li Treg细胞池的ETREG平衡。此外，我们定位 该DR3通过多种机制起作用，以改变IL-2R的产出，以调节IL-10 –的发展 产生ETREG细胞。我们建议，ETREG细胞开发的主要驱动力是STAT3输出的增加 IL-2R通过DR3的作用增强了：（i）增加IL-2R的灵敏度； （ii）降低PSTAT3 降解，从而改变IL-2诱导的STAT5/STAT3比率。最后，我们建议其他TNFRSF DR3表达下降后，成员会促进ETREG细胞维持。我们通过 完全但不是相互依赖的，目的，利用：一种新的生成稳定的结肠炎的方法 Treg细胞离体；原代T细胞中有效基因敲低的新方法；和新的基因目标 鼠标模型来定义控制这些信号通路的收敛的机制 IL10和ETREG程序的转录调节。这些目标的成功完成将建立新的 生物学范例并为内源性IL-10的新型治疗方法提供信息 ETREG细胞的分化和功能增强以治疗人IBD。