Regulation and function of nonlymphoid organ CD103+ dendritic cells

非淋巴器官CD103树突状细胞的调节和功能

• 批准号: 10469028
• 负责人: Stephanie S Watowich
• 金额: $ 48.11万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-24 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10469028
• 关键词: Address; Affect; Agonist; Antigen-Presenting Cells; Antigens; Award; Blocking Antibodies; CD8-Positive T-Lymphocytes; CTLA4 blockade; CTLA4 gene; Cancer Control; Cell physiology; Cells; Cellular biology; Citrobacter rodentium; Colon; Communities; Cross Presentation; Data; Dendritic Cells; Disease; Gastrointestinal tract structure; Gene Deletion; Generations; Goals; Growth; Health; Homeostasis; Hypersensitivity; ITGAX gene; Immune; Immune Tolerance; Immune response; Immunity; Immunologic Memory; Individual; Infection; Inflammation; Inflammatory Response; Intestines; Knowledge; Left; Major Histocompatibility Complex; Mediating; Modeling; Mus; Myeloid Cells; Myelopoiesis; Organ; Peripheral; Population; Production; Regulation; Role; STAT3 gene; Signal Transduction; Stat3 protein; Stimulus; Structure; T cell response; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; TLR3 gene; Testing; Therapeutic; Tissues; Toll-like receptors; Toxic effect; Tumor Immunity; Work; XCR1 gene; adaptive immune response; adaptive immunity; anti-CTLA-4 therapy; cell type; commensal microbes; cytokine; dysbiosis; enteric pathogen; extracellular; gastrointestinal; gut microbiome; gut microbiota; host microbiome; immune checkpoint blockade; immune-related adverse events; inflammatory disease of the intestine; insight; macrophage; microbial; microbiota; mouse model; novel; novel strategies; novel therapeutics; pathogen; prevent; response; transcription factor

PROJECT SUMMARY/ABSTRACT Dendritic cells (DCs) comprise critical antigen (Ag) presenting immune cells, which are important for regulating adaptive immunity, immune tolerance, immunological memory, and innate responses. The type 1 conventional DC (cDC1) subset is highly proficient in Ag cross-presentation on major histocompatibility complex class I (MHC-I) and induction of CD8+ T lymphocytes specific for extracellular Ag. Accordingly, significant effort has been applied toward understanding roles for cDC1s in anti-tumor immunity. By contrast, major gaps in knowledge center on cDC1 function in peripheral tissues such as the gastrointestinal (GI) tract. In the first project period of this award, we discovered key immune-regulatory functions for the cytokine-activated signal transducer and activator of transcription 3 (STAT3) in cDC1s. Our work also revealed a protective role for STAT3 in CD11c+ cells, comprising multiple Ag-presenting subsets including cDC1s. We showed STAT3- deficiency in CD11c+ cells cooperates with therapeutic T cell activation by anti-cytotoxic T-lymphocyte- associated protein 4 (CTLA-4) blockade to drive severe intestinal inflammation and tissue destruction. Furthermore, we found STAT3-deficiency in CD11c+ cells influences the composition and complexity of the intestinal microbiome. Using a novel model to delete STAT3 in cDC1s, we recently showed STAT3 restrains cDC1-mediated GI inflammation. Taken together, our results suggest cDC1s control intestinal inflammatory responses and mediate key interactions with the host microbiome via STAT3-intrinsic mechanisms, yet major gaps in knowledge center on the contribution of cDC1s to intestinal immunity and inflammation, or how this population is modulated by or affects the commensal microbiota. To address these gaps, we will test the central hypothesis that cDC1s direct intestinal immune responses to maintain homeostasis; overactivation of cDC1s by loss of STAT3 potentiates intestinal inflammation in homeostasis or upon challenge with immune- activating stimuli (e.g., CTLA-4, infection) and disrupts the commensal microbiota. This hypothesis will be examined in three aims: 1) Delineate roles for cDC1s and cDC1-intrinsic STAT3 in colon inflammation and response to CTLA-4 therapy; 2) Determine the consequences of cDC1- and cDC1-intrinsic STAT3-deficiency upon T cell generation and T cell activity in the colon; and 3) Evaluate the interaction of cDC1s and cDC1- intrinsic STAT3 with the gut microbiome and control of GI pathogen-driven inflammation. Completion of this project will reveal key facets of intestinal immunity that are currently unknown, including the contribution of cDC1s to intestinal immunity and roles for cDC1-intrinsic STAT3 in these responses. Our studies will provide new basic insights into cDC1 biology and may aid in identifying approaches to mitigate intestinal inflammatory disorders or immune-related adverse events (irAEs) associated with CTLA-4 immune checkpoint blockade.

项目总结/摘要 树突状细胞（DC）包含关键抗原（Ag）呈递免疫细胞，其对于调节免疫应答是重要的。 适应性免疫、免疫耐受、免疫记忆和先天反应。1型常规 DC（cDC 1）亚群在主要组织相容性复合体I类上的Ag交叉呈递中高度熟练 （MHC-I）和对细胞外Ag特异性的CD 8 + T淋巴细胞的诱导。因此，作出了重大努力， 已应用于了解cDC 1在抗肿瘤免疫中的作用。相比之下， cDC 1在外周组织如胃肠道（GI）中的功能。上 在这个奖项的项目期间，我们发现了关键的免疫调节功能的丝氨酸激活的信号 cDC 1中的转录因子和转录激活因子3（STAT 3）。我们的工作还揭示了一种保护作用， CD 11 c+细胞中的STAT 3，包含多个Ag呈递亚群，包括cDC 1。我们发现STAT 3- CD 11 c+细胞的缺陷与抗细胞毒性T淋巴细胞的治疗性T细胞活化协同作用， 相关蛋白4（CTLA-4）阻断，以驱动严重的肠道炎症和组织破坏。 此外，我们发现CD 11 c+细胞中的STAT 3缺陷会影响CD 11 c+细胞的组成和复杂性。 肠道微生物组使用一种新的模型来删除cDC 1中的STAT 3，我们最近发现STAT 3抑制 cDC 1介导的GI炎症。总之，我们的结果表明cDC 1控制肠道炎症 反应并通过STAT 3-内在机制介导与宿主微生物组的关键相互作用，但主要 关于cDC 1对肠道免疫和炎症的贡献，或者这是如何发生的， 种群受肠道微生物群调节或影响肠道微生物群。为了解决这些差距，我们将测试 cDC 1 s指导肠道免疫应答以维持稳态的中心假设; STAT 3缺失导致的cDC 1在体内平衡或免疫刺激后增强肠道炎症 激活刺激（例如，CTLA-4，感染）并破坏肠道微生物群。这一假设将是 在三个目标中进行检查：1）描述cDC 1和cDC 1-内在STAT 3在结肠炎症中的作用， 对CDCTLA-4治疗的反应; 2）确定cDC 1和cDC 1内在STAT 3缺陷的后果 在结肠中的T细胞产生和T细胞活性;和3）评估cDC 1和cDC 1 - 1的相互作用。 内源性STAT 3与肠道微生物组和GI病原体驱动的炎症的控制。完成本 该项目将揭示目前未知的肠道免疫的关键方面，包括 cDC 1对肠道免疫的作用以及cDC 1-内在STAT 3在这些反应中的作用。我们的研究将提供 对cDC 1生物学的新的基本见解，可能有助于确定减轻肠道炎症的方法 疾病或免疫相关的不良事件（irAE）与CDCTLA-4免疫检查点阻断相关。

项目成果

Histone Deacetylase Inhibitors and IL21 Cooperate to Reprogram Human Effector CD8+ T Cells to Memory T Cells.

组蛋白脱乙酰酶抑制剂和 IL21 协同将人类效应 CD8 T 细胞重编程为记忆 T 细胞。

• DOI: 10.1158/2326-6066.cir-19-0619
• 发表时间: 2020
• 期刊: Cancer immunology research
• 影响因子: 10.1
• 作者: Wang,Junmei;Hasan,Farah;Frey,AmandaC;Li,HaiyanS;Park,Jungsun;Pan,Ke;Haymaker,Cara;Bernatchez,Chantale;Lee,DeanA;Watowich,StephanieS;Yee,Cassian
• 通讯作者: Yee,Cassian

Molecular regulation of dendritic cell development and function in homeostasis, inflammation, and cancer.

• DOI: 10.1016/j.molimm.2018.01.014
• 发表时间: 2019-06
• 期刊: Molecular immunology
• 影响因子: 3.6
• 作者: Chrisikos TT;Zhou Y;Slone N;Babcock R;Watowich SS;Li HS
• 通讯作者: Li HS

Mesenchymal stem cells and their therapeutic applications in inflammatory bowel disease.

间充质干细胞及其在炎症性肠病中的治疗应用

• DOI: 10.18632/oncotarget.16682
• 发表时间: 2017-06-06
• 期刊: Oncotarget
• 作者: Mao F;Tu Q;Wang L;Chu F;Li X;Li HS;Xu W
• 通讯作者: Xu W

STAT3 signaling in immunity.

• DOI: 10.1016/j.cytogfr.2016.05.001
• 发表时间: 2016-10
• 期刊: CYTOKINE & GROWTH FACTOR REVIEWS
• 影响因子: 13
• 作者: Hillmer, Emily J.;Zhang, Huiyuan;Li, Haiyan S.;Watowich, Stephanie S.
• 通讯作者: Watowich, Stephanie S.

Bypassing STAT3-mediated inhibition of the transcriptional regulator ID2 improves the antitumor efficacy of dendritic cells.

• DOI: 10.1126/scisignal.aaf3957
• 发表时间: 2016-09-27
• 期刊: Science signaling
• 影响因子: 7.3
• 作者: Li HS;Liu C;Xiao Y;Chu F;Liang X;Peng W;Hu J;Neelapu SS;Sun SC;Hwu P;Watowich SS
• 通讯作者: Watowich SS