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.

项目总结/摘要 驻留在屏障组织中的组织驻留记忆T（TRM）细胞在病原体感染后立即响应 遭遇诱导TRM细胞已经成为疫苗开发的优先事项，以对抗传染病， 癌症免疫疗法减毒革兰氏阴性细菌病原体假结核耶尔森氏菌（Yptb） 将在此作为新的疫苗载体进行评估，以产生抗原特异性肠CD 8 + TRM细胞。作为稀有 病原体，Yptb主要引起免疫功能正常的人的自限性肠系膜淋巴结炎， 可以用抗生素治疗Yptb亚致死性感染C57 BL/6小鼠可诱导产生大量H-2Kb限制性CD 8 + T细胞 特异于细菌表位YopE 69 -77的细胞应答。在食源性感染后，两种不同的Yptb亚群- 在肠组织中鉴定出特异性CD 8 + TRM细胞：散在的CD 103+和成簇的CD 103-。 细胞CD 103+细胞依赖于转化生长因子-b（TGF β），而CD 103-细胞需要 干扰素-b（IFNb）和白细胞介素-12（IL-12），主要由CCR 2依赖性炎症因子产生的炎性细胞因子， 细胞 Yptb的几个独特的特征表明，这种以前被忽视的病原体是有利的， 将其转化到疫苗载体中。Yptb利用3型分泌系统（T3 SS）注射一组 6-7毒性效应蛋白，统称为Yops，从细菌直接进入真核细胞的胞质溶胶 在感染期间。通过Yptb T3 SS注射这些Yop效应物是接触依赖性的，并且随后 在小鼠感染中，高百分比的吞噬细胞是目标。因此，Yptb疫苗 载体将抗原蛋白直接引入吞噬性抗原呈递细胞的胞质溶胶中，而不需要 需要操纵真核细胞的基因组或转录组。在此建议开展研究， 研究以了解两种类型的TRM生成的细菌和细胞决定因素。此外，本发明还提供了一种方法， 因为Yop效应子干扰宿主免疫应答，所以将努力减弱Yptb， 的疫苗载体，并通过灭活相关的Yop效应子来增加其免疫原性。 此外，由于细胞毒性CD 8 + T细胞应答是控制Yptb所必需的，即使在保护性CD 8 + T细胞的存在下也是如此。 抗体应答，减毒的Yptb疫苗载体可以重复引入以引发抗体应答的可能性。 将评价具有额外抗原特异性的TRM细胞。完成这里提出的研究将设置 为研制新型减毒活疫苗奠定了基础，这是肠道TRM细胞产生所迫切需要的。