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.

项目概要/摘要 驻留在屏障组织中的组织驻留记忆 T (TRM) 细胞在病原体出现后立即做出反应 遇到。诱导 TRM 细胞已成为对抗传染病和疫苗开发的优先事项 在癌症免疫治疗中。活减毒革兰氏阴性细菌病原体假结核耶尔森氏菌 (Yptb) 将在这里作为新的疫苗载体进行评估，以产生抗原特异性肠道 CD8+ TRM 细胞。作为稀有的 Yptb 是一种病原体，在免疫能力正常的人类中主要引起自限性肠系膜淋巴结炎，并且是 可以用抗生素治疗。 C57BL/6 小鼠中 Yptb 亚致死感染引发大量 H-2Kb 限制性 CD8+ T 针对细菌表位 YopE69-77 的细胞反应。食源性感染后，Yptb 的两个不同亚型- 在肠道组织中鉴定出特异性 CD8+ TRM 细胞：分散的 CD103+ 和聚集的 CD103neg 细胞。 CD103+ 细胞依赖于转化生长因子-b (TGFb)，而 CD103neg 细胞则需要 干扰素-b (IFNb) 和白细胞介素-12 (IL-12)，炎症细胞因子主要由 CCR2 依赖性产生 细胞。 Yptb 的几个独特特征表明，这种以前被忽视的病原体具有优势 转化为疫苗载体的位置。 Yptb 利用 3 型分泌系统 (T3SS) 注射一组 6-7 个毒性效应蛋白，统称为 Yops，从细菌直接进入真核细胞的细胞质 感染期间。这些 Yop 效应器通过 Yptb T3SS 的注入依赖于接触并遵循 在小鼠感染中，高比例的吞噬细胞是目标之一。因此，基于 Yptb 的疫苗 载体将抗原蛋白直接引入吞噬抗原呈递细胞的胞质溶胶中，无需 需要操纵真核细胞的基因组或转录组。在此提出研究以启动 调查以了解两种类型 TRM 生成的细菌和细胞决定因素。此外， 由于 Yop 效应子会干扰宿主免疫反应，因此将努力减弱 Yptb- 基于疫苗载体并通过灭活相关 Yop 效应子来增加其免疫原性。 此外，因为即使在保护性存在的情况下，也需要细胞毒性 CD8+ T 细胞反应来控制 Yptb 抗体反应，可以反复引入减毒 Yptb 疫苗载体以引发抗体反应 将评估具有额外抗原特异性的 TRM 细胞。完成此处提出的研究将确定 为开发肠道TRM细胞生成急需的新型减毒活疫苗奠定了基础。