Organ-specific CD4 T cell responses regulate Salmonella persistence

描述（由申请人提供）：伤寒，由细胞内细菌伤寒沙门氏菌引起，每年在全世界造成50多万人死亡。在许多感染者中，沙门氏菌在面对强有力的适应性免疫反应时仍然存在，通常在特定器官（如肝脏，脾脏和肠系膜淋巴结）内维持水库。虽然它是已知的，IFN-？和CD 4 T细胞是控制沙门氏菌感染所必需的，但调节细菌持久性的免疫机制仍不清楚。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CD 4 T细胞可以防止新的沙门氏菌感染，而来自肝脏的T细胞实际上会加重感染。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。本项目的主要目标是检验我们的中心假设，即持续性沙门氏菌感染是由于肝脏中沙门氏菌特异性CD 4 T细胞的抑制性质，而次级淋巴组织中的效应功能。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细胞库和（2）淋巴组织和肝组织之间抗原呈递的差异。这一假设是基于我们强有力的初步数据。具体而言，该项目将1）确定来自次级淋巴组织和肝脏的沙门氏菌特异性CD 4 T细胞如何影响沙门氏菌体内持久性; 2）确定新的胸腺衍生的CD 4 T细胞对沙门氏菌体内持久性的贡献; 3）确定器官特异性抗原呈递如何影响持续感染期间沙门氏菌特异性CD 4 T细胞的功能表型。这项研究是创新性的，因为它结合了使用我们实验室制造的特异性MHC II类四聚体评估内源性CD 4 T细胞反应的能力，以及对细菌的解剖位置如何影响CD 4 + T细胞对持续感染的反应的新见解。这一贡献是重要的，因为它将提供新的见解，免疫机制的基础上持久的细胞内细菌在体内，以及定义的作用组织微环境在调节病原体特异性免疫反应。最终，这些知识可以作为一个跳板，了解组织环境如何塑造内源性抗原特异性反应，其他持久的人类细菌病原体。

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.