Generation of CD8+ Tissue-Resident Memory T cell response during Yersinia pseudotuberculosis foodborne infection

假结核耶尔森菌食源性感染期间 CD8 组织驻留记忆 T 细胞反应的产生

• 批准号: 10572273
• 负责人: Yue Zhang
• 金额: $ 23.93万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-26 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10572273
• 关键词: Antibiotic Therapy; Antibiotics; Antibody Response; Antigen-Presenting Cells; Antigenic Specificity; Antigens; Attenuated; Attenuated Vaccines; Bacteria; Bacterial Vaccines; C57BL/6 Mouse; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell secretion; Cells; Characteristics; Communicable Diseases; Cross Presentation; Cytosol; Dendritic Cells; Economics; Epitopes; Eukaryotic Cell; Foundations; Generations; Genes; Genome; Human; Immune response; Immunocompetent; Individual; Infection; Inflammatory; Injections; Interferon-beta; Interleukin-12; Intestines; Intravenous; Investigation; Memory; Mesenteric Lymphadenitis; Mus; Mutation; Pasteurella pseudotuberculosis; Phagocytes; Positioning Attribute; Production; Proteins; Role; Signal Pathway; T cell response; Tissues; Transforming Growth Factors; Transportation; Type III Secretion System Pathway; Vaccination; Virulence; Virus Diseases; Yersinia pseudotuberculosis Infections; cancer immunotherapy; combat; cytokine; cytotoxic CD8 T cells; foodborne infection; immunogenicity; improved; mouse model; mutant; novel vaccines; pathogen; pathogenic bacteria; tissue resident memory T cell; transcriptome; vaccine development; vector vaccine; vector-based vaccine

Project Summary/Abstract The tissue resident memory T (TRM) cells that reside at barrier tissues respond immediately following pathogen encounter. Eliciting TRM cells has become a priority in vaccine development to combat infectious diseases and in cancer immunotherapy. Live attenuated Gram-negative bacterial pathogen Yersinia pseudotuberculosis (Yptb) will be evaluated here as a new vaccine vector to produce antigen-specific intestinal CD8+ TRM cells. As a rare pathogen, Yptb causes mostly self-limited mesenteric lymphadenitis in immune competent humans and is treatable with antibiotics. Sub-lethal infection with Yptb in C57BL/6 mice elicits a large H-2Kb-restricted CD8+ T cell response specific to bacterial epitope YopE69-77. Following foodborne infection, two different subsets of Yptb- specific CD8+ TRM cells were identified in intestinal tissues: the scattered CD103+ and the clustered CD103neg cells. The CD103+ cells depend on transforming growth factor-b (TGFb) and the CD103neg cells require interferon-b (IFNb) and interleukin-12 (IL-12), inflammatory cytokines mostly generated from CCR2-dependent cells. Several unique characteristics of Yptb suggest that this previously overlooked pathogen is at an advantageous position to be transformed into a vaccine vector. Yptb utilizes a type 3 secretion system (T3SS) to inject a set of 6-7 toxic effector proteins, collectively called Yops, from the bacterium directly into the cytosol of eukaryotic cells during infection. Injection of these Yop effectors through the Yptb T3SS is contact dependent and following mouse infection, a high percentage of phagocytes are among the targets. Therefore, the Yptb-based vaccine vector introduces antigenic proteins directly into the cytosol of phagocytic antigen-presenting cells without the need to manipulate the genome or transcriptome of eukaryotic cells. Studies are proposed here to initiate investigation to understand the bacterial and cellular determinants of the two types of TRM generation. In addition, because the Yop effectors interfere with host immune responses, efforts will be made to attenuate the Yptb- based vaccine vector and increase its immunogenicity through inactivation of the relevant Yop effectors. Moreover, because cytotoxic CD8+ T cell response is required to control Yptb even in the presence of protective antibody response, the possibility that the attenuated Yptb vaccine vector can be introduced repeatedly to elicit TRM cells with additional antigenic specificity will be evaluated. Accomplishing the studies proposed here will set the foundation to develop a new type of live attenuated vaccine that is urgently needed for gut TRM cell generation.

项目摘要/摘要 驻留在障碍组织的组织驻留记忆t（TRM）细胞立即在病原体后反应 遇到。引起TRM细胞已成为疫苗发育的优先事项，以打击感染性疾病和 在癌症免疫疗法中。活细胞性细菌病原体耶尔森氏病（YPTB） 此处将作为一种新的疫苗载体评估，以产生抗原特异性肠CD8+ TRM细胞。罕见 病原体，YPTB引起免疫胜任人的自限性肠系膜淋巴结炎，IS 可以用抗生素治疗。在C57BL/6小鼠中YPTB的亚致死感染引起了大H-2KB限制的CD8+ T 细胞反应特有细菌表位YOPE69-77。食源性感染后，YPTB-两个不同的子集 - 在肠道组织中鉴定了特定的CD8+ TRM细胞：散射的CD103+和聚集的CD103NEG 细胞。 CD103+细胞取决于转化生长因子-B（TGFB），CD103NEG细胞需要 干扰素B（IFNB）和白介素12（IL-12），炎性细胞因子主要由CCR2依赖性产生 细胞。 YPTB的几个独特特征表明，这种先前被忽视的病原体处于有利 将要转化为疫苗载体的位置。 YPTB利用3型分泌系统（T3SS）注入一组 6-7的有毒效应蛋白，统称为YOPS，直接从细菌直接进入真核细胞的细胞质 在感染期间。通过YPTB T3SS注入这些YOP效应子是接触依赖性和遵循的 小鼠感染是靶标之一。因此，基于YPTB的疫苗 载体将抗原蛋白直接引入吞噬细胞抗原细胞的细胞质中，而没有该细胞 需要操纵真核细胞的基因组或转录组。这里提出了研究来启动 研究两种类型的TRM生成的细菌和细胞决定因素。此外， 由于YOP效应子干扰宿主免疫反应，因此将努力减轻YPTB- 基于疫苗载体并通过失活相关的YOP效应子来增加其免疫原性。 此外，由于细胞毒性CD8+ T细胞响应即使在有保护性的情况下也需要控制YPTB 抗体反应，可以反复引入减毒的YPTB疫苗载体的可能性以引起 将评估具有其他抗原特异性的TRM细胞。完成此处提出的研究将设定 迫切需要肠道TRM细胞生成需要的新型活疫苗的基础。