Regulation of CD4+ T cells in Cryptosporidium infection

CD4 T 细胞在隐孢子虫感染中的调节

• 批准号: 10603017
• 负责人: Ian Cohn
• 金额: $ 5.27万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10603017
• 关键词: Address; Antigen Presentation; Antigens; Architecture; Blocking Antibodies; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell physiology; Cells; Cessation of life; Child; Childhood; Cryptosporidiosis; Cryptosporidium; Data; Defect; Dendritic Cells; Development; Diarrhea; Disease; Engineering; Epithelial Cells; Flow Cytometry; Generations; Genes; Genetic; Human; IL17 gene; Immune system; Immunity; Immunocompetent; Immunocompromised Host; Immunology; Individual; Infection; Inflammation; Interferon Type II; Interleukin-12; Intestinal Diseases; Intestinal parasite; Intestines; Investigation; Knock-out; Knowledge; Learning; Maintenance; Malnutrition; Measures; Modeling; Morbidity - disease rate; Mucous Membrane; Mus; Parasite Control; Parasites; Parasitology; Phenotype; Physicians; Population; Prevention; Production; Regulation; Resistance to infection; Rest; Role; Scientist; Small Intestines; Source; Sterility; System; T cell regulation; T cell response; T-Lymphocyte; Testing; Th1 Cells; Training; Transgenic Organisms; Work; adaptive immune response; cytokine; diarrheal disease; enteric infection; genetic approach; high dimensionality; in vivo; interleukin-22; intestinal epithelium; large scale data; mortality; mouse genetics; mouse model; novel; pathogen; response; single-cell RNA sequencing; skills; transcription factor; vaccine development

Project Summary The apicomplexan parasite Cryptosporidium is a leading cause of diarrhea and death in immunocompromised individuals and malnourished children globally. Control of Cryptosporidium requires CD4+ T cells and the cytokine interferon-γ (IFN-γ), however there are significant gaps in our understanding of the regulation of T cell responses against the parasite. This is in large part due to difficulties analyzing T cell populations in the gut. By engineering Cryptosporidium to express MHCII-restricted model antigens, I can identify parasite-specific CD4+ T cells within the gut. Using this system, I have found that CD4+ T cell responses require type 1 conventional dendritic cells (cDC1s) despite their better-studied role in CD8+ rather than CD4+ T cell responses. In addition, I have found evidence for a Th17 response elicited by infection, pointing to an IFN-γ- independent but T cell-dependent mechanism of control of the parasite that has remained elusive. I will utilize a combination of novel transgenic parasites, genetic mouse models, single-cell RNA sequencing, and high- dimensional flow cytometry to test which cDC subset(s) are required for CD4+ T cell responses to Cryptosporidium (SA1), and to investigate the IFN-γ-independent, CD4+ T cell-dependent mechanism(s) of control with a focus on Th17 responses (SA2). These studies will provide an opportunity to train in cross- disciplinary approaches in parasitology and immunology to better understand how immunity to infection in the gut is regulated. The studies proposed here will impact our fundamental understanding of mucosal immunology and drive treatment and prevention for an important source of childhood mortality.

项目摘要 顶端复合体寄生虫隐孢子虫是免疫受损患者腹泻和死亡的主要原因 全球范围内的个人和营养不良儿童。控制隐孢子虫需要CD4+T细胞和 细胞因子干扰素-γ(干扰素-γ)，然而，我们对T细胞的调节有很大的认识上的差距 对寄生虫的反应。这在很大程度上是由于diffi邪教分析肠道中的T细胞群。 通过工程隐孢子虫表达mhcⅡ限制性模式抗原，我可以鉴定寄生虫物种fic。 肠道内的CD4+T细胞。使用这个系统，我发现CD4+T细胞反应需要1型 传统的树突状细胞(CDC1s)，尽管它们在CD8+T细胞中的作用比在CD4+T细胞中的作用研究得更好 回应。此外，我还发现了感染引发Th17反应的证据，指向一种干扰素-γ- 控制寄生虫的独立但依赖于T细胞的机制仍然难以捉摸。我会利用 一种新的转基因寄生虫、遗传小鼠模型、单细胞RNA测序和高... 用三维fl技术检测哪些CDC亚群(S)是CD_4+T细胞应答所必需的 隐孢子虫，并探讨干扰素-γ非依赖性，CD+T细胞依赖的机制(S)。 控制，重点是Th17反应(SA2)。这些研究将提供一个机会，以训练交叉- 寄生虫学和免疫学的学科方法，以更好地了解人类对感染的免疫力是如何 肠子是有规律的。这里提出的研究将影响我们对粘膜的基本理解 免疫学和驱动力治疗和预防儿童死亡的一个重要来源。