Organ-specific CD4 T cell responses regulate Salmonella persistence

描述(申请人提供)：伤寒是由细胞内细菌伤寒沙门氏菌引起的，每年导致全球50多万人死亡。在一些受感染的人中，沙门氏菌面对强大的适应性免疫反应持续存在，通常维持肝、脾和肠系膜淋巴结等特定器官的储存库。虽然已知干扰素-？而CD4T细胞是控制沙门氏菌感染所必需的，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，来自淋巴组织的内源性沙门氏菌特异性CD4T细胞可以预防新的沙门氏菌感染，而来自肝脏的那些细胞实际上会加剧感染。我们还发现淋巴组织和肝脏之间重要的功能和表型差异，这可能有助于细菌的持久性。这个项目的主要目的是检验我们的中心假设，即持续沙门氏菌感染是由于肝脏中沙门氏菌特异性CD4T细胞的抑制性质，而不是次级淋巴组织中的效应器功能。我们假设持续性沙门氏菌感染取决于两个因素：(1)新的胸腺来源的T细胞进入效应T细胞池；(2)淋巴组织和肝脏组织之间的抗原提呈差异。这一假设是建立在我们强大的初步数据基础上的。具体地说，这个项目将1)确定来自次级淋巴组织和肝脏的沙门氏菌特异性CD4T细胞如何影响体内沙门氏菌的持久性；2)确定新的胸腺来源的CD4T细胞在体内对沙门氏菌持久性的贡献；以及3)确定器官特异性抗原呈递如何在持续感染期间影响沙门氏菌特异性CD4T细胞的功能表型。提出的这项研究是创新的，因为它结合了使用我们实验室制造的特定MHC II类四聚体评估内源性CD4T细胞反应的能力，以及对细菌的解剖位置如何影响CD4T细胞对持续感染的反应的新见解。这一贡献意义重大，因为它将为细胞内细菌在体内持续存在的免疫学机制提供新的见解，并确定组织微环境在调节病原体特异性免疫反应中所起的作用。最终，这些知识可以作为一个跳板，以了解组织环境如何塑造对其他持久性人类细菌病原体的内源性抗原特异性反应。

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.