Dysregulated gut-microbe CD4 T cell interactions with Aging

失调的肠道微生物 CD4 T 细胞与衰老的相互作用

• 批准号: 9895280
• 负责人: Cara C. Wilson
• 金额: $ 23.33万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9895280
• 关键词: Acute-Phase Proteins; Address; Age; Aging; Animal Model; Apoptotic; BCL2 gene; Bacteria; Biological Markers; Blood Coagulation Factor; Butyrates; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CTLA4 gene; Cardiovascular Diseases; Cell Communication; Cell model; Cell physiology; Cells; Chronic; Clinical; Colon; Comorbidity; Data; Dose; Elderly; Enteral; Epithelial; Exposure to; Expression Profiling; Feces; Functional disorder; Future; Gene Expression; Goals; Gut Mucosa; Helper-Inducer T-Lymphocyte; Homeostasis; Human; Immune; Immune system; Immunity; Immunosuppression; Impaired cognition; Impairment; In Vitro; Inflammaging; Inflammation; Inflammatory; Inflammatory Response; Inflammatory disease of the intestine; Interferon Type II; Interleukin-10; Interleukin-17; Intestinal Mucosa; Intestines; Knowledge; Lamina Propria; Lead; Link; Malignant Neoplasms; Memory; Microbe; Mononuclear; Mucositis; Mucous Membrane; Older Population; Pathway interactions; Phenotype; Physiological; Plasma; Play; Population; Production; Proliferating; Role; SLEB2 gene; Shapes; Study models; T-Lymphocyte; Tissues; Volatile Fatty Acids; age effect; age related; bacterial community; colon microbiome; commensal bacteria; cytokine; design; differential expression; dysbiosis; enteric pathogen; exhaustion; fecal microbiome; genetic signature; gut microbes; gut microbiome; immune activation; immune checkpoint; immune function; immunoregulation; insight; intestinal homeostasis; microbial; microbiome; mortality; novel; pathobiont; pathogen; peripheral blood; response; transcriptomics; translational impact

ABSTRACT Physiological aging is associated with a low grade chronic inflammatory state which has been link to numerous geriatric comorbid conditions. While there are likely multiple contributors to this “inflammaging” phenotype, a number of recent animal model studies have implicated a breakdown in gut homeostasis as a key factor. We established that human plasma biomarkers indicative of gut epithelial barrier damage and gut microbial translocation increased with age and correlated with markers of systemic immune activation thus showing that age-related disruption of human gut homeostasis is linked to inflammaging. Prior studies have shown that the fecal microbiome is altered or “dysbiotic” with age, with an increase in enteric commensal bacteria capable of inducing inflammation (pathobionts) and a decrease in immune regulatory bacterial metabolites (e.g. the short chain fatty acid, butyrate). Gut CD4 T cells are the largest gut mucosal T cell population and play a vital role in maintaining homeostasis by protecting against gut pathogens or translocating microbes. We demonstrated that human gut lamina propria (LP) CD4+ T cells become activated, produce inflammatory cytokines (IL-17, IFNγ), and proliferate upon exposure to enteric pathobiont bacteria in vitro. We now have preliminary data demonstrating that butyrate inhibits these bacteria-driven inflammatory responses and induces expression of regulatory molecules such as PD1 and IL-10. In pilot ex vivo studies we show that older age is associated with an accumulation of IL-17-producing T helper (Th) cells (Th17), especially those that co-produce IFNγ, a known inflammatory subset. Furthermore, older LP CD4 T cells expressed significantly lower levels of the co-inhibitory immune checkpoints PD1 and CTLA4 than younger LP CD4 T cells and higher levels of anti-apoptotic Bcl-2. This finding is counterintuitive as increased expression of PD1 and CTLA4 have been associated with exhaustion of peripheral blood T cells. Our overarching hypothesis is that age-associated intrinsic immune dysregulation (low co-inhibitory immune checkpoint expression) of gut CD4 T cells combined with pro- inflammatory (high pathobiont, low butyrate) gut dysbiosis will result in expansion of inflammatory Th17 cells. To explore age-associated gut CD4 T cell/microbe interactions, we propose 2 aims that will utilize an ex vivo human colon LP mononuclear cell model to gain insights into the effects of aging on microbiome-gut CD4 T cells interactions. In Aim 1, we will determine whether distinct colonic Th cells differentially express a dysregulated aging immune phenotype and identify a corresponding transcriptomics profile linked to this phenotype. In Aim 2 we will evaluate the impact of aging on immune function of colonic Th subsets in response to colonic microbiome-associated immune-stimulatory and immune-regulatory factors. These studies will provide critically needed information on the impact of age on gut CD4 T cell immunity in the setting of age-associated dysbiosis. The insights gained will support future studies in older populations designed to probe the contribution of specific pathways of gut inflammation to systemic inflammation and comorbidities.

摘要 生理老化与低度慢性炎症状态有关，其与许多疾病有关。 老年合并症。虽然这种“炎症”表型可能有多种贡献者， 最近的一些动物模型研究表明，肠道内稳态的破坏是一个关键因素。我们 建立了指示肠上皮屏障损伤和肠微生物的人血浆生物标志物， 易位随着年龄的增长而增加，并与全身免疫激活的标志物相关，因此表明， 与年龄相关的人体肠道内稳态的破坏与炎症有关。先前的研究表明， 粪便微生物组随着年龄的增长而改变或“生态失调”，肠道细菌的增加能够 诱导炎症（致病菌）和免疫调节细菌代谢物（例如短 链脂肪酸、丁酸盐）。肠道CD 4 T细胞是最大的肠道粘膜T细胞群，在肠道免疫中起着至关重要的作用。 通过防止肠道病原体或移位的微生物来维持体内平衡。我们证明了 人肠道固有层（LP）CD 4 + T细胞被激活，产生炎性细胞因子（IL-17、IFNγ）， 并在体外暴露于肠道致病菌时增殖。我们现在有了初步数据 表明丁酸盐抑制这些细菌驱动的炎症反应并诱导 调节分子如PD 1和IL-10。在初步的体外研究中，我们发现年龄较大与 产生IL-17的辅助性T（Th）细胞（Th 17）的积累，特别是那些共同产生IFNγ的细胞，这是已知的 炎症亚群此外，年龄较大的LP CD 4 T细胞表达的共抑制因子水平显著较低。 免疫检查点PD 1和CTLA 4比年轻的LP CD 4 T细胞和更高水平的抗凋亡Bcl-2。 这一发现是违反直觉的，因为PD 1和CTLA 4表达的增加与疲劳有关。 外周血T细胞。我们的总体假设是，年龄相关的内在免疫 肠道CD 4 T细胞的调节异常（低共抑制免疫检查点表达）， 炎性（高致病菌，低丁酸盐）肠道生态失调将导致炎性Th 17扩增 细胞为了探索与年龄相关的肠道CD 4 T细胞/微生物相互作用，我们提出了2个目标，将利用一种前 体内人结肠LP单核细胞模型，以深入了解衰老对微生物组-肠道CD 4的影响 T细胞相互作用。在目标1中，我们将确定不同的结肠Th细胞是否差异表达一种免疫应答。 失调的衰老免疫表型，并确定与此相关的相应转录组学谱 表型在目标2中，我们将评估衰老对结肠Th亚群免疫功能的影响， 结肠微生物组相关的免疫刺激和免疫调节因子。这些研究将提供 在年龄相关的疾病背景下，年龄对肠道CD 4 T细胞免疫力影响的迫切需要的信息 生态失调所获得的见解将支持未来在老年人群中进行的旨在探索 肠道炎症到全身炎症和合并症的特定途径。