Organ-specific CD4 T cell responses regulate Salmonella persistence

器官特异性 CD4 T 细胞反应调节沙门氏菌的持久性

• 批准号: 8578801
• 负责人: James B McLachlan
• 金额: $ 35.37万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-18 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8578801
• 关键词: Address; Affect; Antigen Presentation; Antigen-Presenting Cells; Antigens; Bacteria; Bacterial Infections; CD4 Positive T Lymphocytes; Cell physiology; Cells; Cessation of life; Data; Dendritic Cells; Development; Emigrant; Environment; Exhibits; Gallbladder; Goals; Helicobacter; Hepatic Tissue; Human; Immune; Immune response; Immune system; Immunity; Infection; Interferons; Interleukin-10; Intervention; Knowledge; Kupffer Cells; Laboratories; Liver; Location; Lymphoid; Lymphoid Tissue; MHC Class II Genes; Mesentery; Mission; Modeling; Mus; Mycobacterium tuberculosis; Nature; Organ; Outcome; Output; Pathogenesis; Peripheral; Phenotype; Play; Pylorus; Research; Role; Salmonella; Salmonella infections; Salmonella typhi; Shapes; Spleen; Sterile coverings; Sterility; T cell response; T-Lymphocyte; Testing; Therapeutic; Thymus Gland; Tissues; Typhoid Fever; Vaccine Therapy; Work; antimicrobial; base; human disease; in vivo; innovation; insight; killings; lymph nodes; mortality; novel; pathogen; prevent; prophylactic; public health relevance; response

DESCRIPTION (provided by applicant): Typhoid fever, caused by the intracellular bacterium Salmonella typhi, is responsible for more than a half million deaths annually worldwide. In a number of infected people, Salmonella bacteria persist in the face of a potent adaptive immune response, generally maintaining reservoirs within specific organs such as the liver, spleen, and mesenteric lymph nodes. While it is known that IFN-? and CD4 T cells are required to control Salmonella infection, the immune mechanisms that regulate bacterial persistence remain unclear. Here, we provide evidence that endogenous Salmonella-specific CD4 T cells from lymphoid tissue protect against new Salmonella infections, while those from the liver actually worsen infection. We also find important functional and phenotypic differences between lymphoid tissues and liver, which may contribute to bacterial persistence. The main goal of this project is to test our central hypothesis that persistent Salmonella infection is due to the suppressive nature of Salmonella-specific CD4 T cells in the liver compared to the effector functions of those in secondary lymphoid tissue. We hypothesize persistent Salmonella infection de- pends upon two factors: (1) new thymus-derived T cells entering the effector T cell pool and (2) differences in antigen presentation between lymphoid and hepatic tissue. This hypothesis is based on our strong preliminary data. Specifically, this project will 1) Define how Salmonella-specific CD4 T cells from secondary lymphoid tis- sues and liver affect Salmonella persistence in vivo; 2) Determine the contribution of new, thymus-derived CD4 T cells to Salmonella persistence in vivo; and 3) Determine how organ-specific antigen presentation affects the functional phenotype of Salmonella-specific CD4 T cells during persistent infection. The research proposed is innovative due to the combination of the ability to assess endogenous CD4 T cell response using specific MHC class II tetramers made in our lab combined with novel insights into how the anatomical location of bacteria impacts CD4+ T cell responses to persistent infection. This contribution is significant because it will provide new insights into immunological mechanisms that underlie the persistence of an intracellular bacterium in vivo, as well as define the role tissue microenvironments play in modulating the pathogen-specific immune response. Ultimately, this knowledge can serve as a springboard for understanding how tissue environment shapes the endogenous antigen-specific response to other persistent human bacterial pathogens.

描述（由申请人提供）：由细胞内细菌沙门氏菌Typhi引起的伤寒热，每年在全球造成超过500万人死亡。在许多受感染的人中，面对有效的适应性免疫反应，沙门氏菌持续存在，通常在特定器官（例如肝脏，脾和肠系膜淋巴结）中保持储层。虽然知道ifn-？需要CD4 T细胞来控制沙门氏菌感染，调节细菌持久性的免疫机制尚不清楚。在这里，我们提供的证据表明，来自淋巴组织组织的内源性沙门氏菌特异性CD4 T细胞可以预防新的沙门氏菌感染，而来自肝脏的新沙门氏菌感染实际上会恶化感染。我们还发现淋巴组织和肝脏之间的重要功能和表型差异，这可能有助于细菌持久性。该项目的主要目的是检验我们的中心假设，即持续的沙门氏菌感染是由于肝脏中沙门氏菌特异性CD4 T细胞的抑制性质，与继发性淋巴组织中的效应子功能相比。我们假设持续的沙门氏菌感染对两个因素进行了影响：（1）新的胸腺来源的T细胞进入效应T细胞池，（2）淋巴机和肝组织之间抗原表现的差异。该假设基于我们强大的初步数据。具体而言，该项目将1）定义来自次生淋巴样和肝脏的沙门氏菌特异性CD4 T细胞如何影响体内沙门氏菌的持久性； 2）确定新的胸腺衍生的CD4 T细胞对体内沙门氏菌持久性的贡献； 3）确定器官特异性抗原表现如何影响持续感染过程中沙门氏菌特异性CD4 T细胞的功能表型。提出的研究具有创新性，这是因为使用我们实验室中制造的特定MHC II类四聚体评估内源性CD4 T细胞反应的能力结合了对细菌的解剖位置如何影响CD4+ T细胞对持续感染的反应如何影响CD4+ T细胞反应。这种贡献很重要，因为它将为体内细胞内细菌持续存在的免疫机制提供新的见解，并定义了组织微环境在调节病原体特异性免疫反应中起作用的作用。最终，这些知识可以用作跳板，以了解组织环境如何塑造对其他持续人类细菌病原体的内源性抗原特异性反应。