Protective CD4+ T cells

描述(申请人提供)：CD4T细胞通过调节B细胞、CD8T细胞和吞噬细胞的功能，在对细胞内和细胞外微生物的适应性免疫反应中发挥主要作用。然而，由分枝杆菌、沙门氏菌和隐球菌引起的吞噬小体感染在CD4T细胞缺陷的艾滋病患者中的流行表明，这些细胞最重要的功能是吞噬细胞激活。然而，人们对这种功能知之甚少，这可能解释了为什么对这些每年导致200万人死亡的病原体没有有效的疫苗。当人们考虑依赖于CD4T细胞的“伴随免疫”的奇怪特征时，这种知识差距的大小就变得显而易见了，这种伴随免疫很可能对所有吞噬体感染起作用。产生干扰素-γ的Th1细胞在感染的初始部位控制吞噬细胞内的感染，并防止它扩散到身体的其他部位。然而，奇怪的是，Th1细胞永远不会从最初的部位清除微生物。事实上，在第二次感染后，Th1细胞需要在原始部位持续感染，以清除身体其他部位的细菌。允许Th1细胞在不消除感染的情况下控制感染的调控机制尚不清楚。此外，如果原始感染被消除，为什么CD4T细胞记忆没有保留，以及为什么持续感染不会导致T细胞耗尽，目前还不清楚。我们将使用一种敏感的多肽：主要组织相容性复合体II(p：MHCII)四聚体细胞浓缩方法来研究内源性CD4T细胞对因摄入伤寒沙门氏菌而引起的典型持续性吞噬感染的反应，以深入了解保护性CD4T细胞是如何产生和发挥作用的。我们将检验我们的观点，即受感染的吞噬细胞独有地呈现p：MHCII复合体，驱动产生干扰素-γ的Th1效应细胞的产生，而不产生依赖于B细胞的滤泡辅助T细胞。我们将探索在初始感染部位被感染的吞噬细胞产生IL-10的可能性，这限制了它们清除感染的能力，并阻止Th1细胞的最终分化，将它们锁定在一种状态，使它们保持对多种保护性吞噬细胞激活细胞因子的能力。我们将确定肠系膜淋巴结中持续感染的产生IL-10的吞噬细胞是否也通过Th1记忆细胞刺激爆发的增殖，Th1记忆细胞定期通过该部位循环，以维持稳定和功能保护的群体。通过一个强大的体内模型系统实现我们的特定目标，可以指导针对这类顽固病原体的疫苗开发。

DESCRIPTION (provided by applicant): CD4+ T cells play a major role in adaptive immune responses to intracellular and extracellular microbes by regulating the functions of B cells, CD8+ T cells, and phagocytes. However, the prevalence of phagosomal infections caused by Mycobacteria, Salmonella, and Cryptococcus in CD4+ T cell-deficient AIDS patients demonstrates that the most important function of these cells is phagocyte activation. Yet this function is poorly understood, which probably explains why no effective vaccines exist for these pathogens that kill at 2 million people every year. The size of this knowledge gap becomes clear when one considers the odd features of CD4+ T cell-dependent "concomitant immunity", which likely operates for all phagosomal infections. IFN-γ producing Th1 cells control the infection within phagocytes at the initial site of infection and prevent it from spreading to other parts of he body. Oddly, however, the Th1 cells never eliminate the microbes from the initial site. Indeed, persistent infection at the original site is required for the Th1 cells to eliminate bacteria from other body sites after a second infection. The regulatory mechanisms that allow Th1 cells to control the infection without eliminating it are not understood. In addition, it is not clear why CD4+ T cell memory is not retained if the original infection is eliminated and why persistent infection does not result in T cell exhaustion. We will use a sensitive peptide: major histocompatibility complex II (p:MHCII) tetramer- based cell enrichment method to study the endogenous CD4+ T cell response to a prototypical persistent phagosomal infection caused by ingestion of Salmonella enterica serovar Typhimuruim (ST) bacteria to gain insight into how protective CD4+ T cells are generated and function. We will test our idea that presentation of p: MHCII complexes exclusively by infected phagocytes drives the generation of IFN-γ-producing Th1 effector cells without generating B cell-dependent follicular helper T cells. We will explore the possibility that infected phagocytes at the site of initial infection produce IL-10, which limis their capacity to clear their infection and prevents terminal differentiation of the Th1 cells, locking them in a state where they retain the capacity to multiple protective phagocyte-activating cytokines. We will determine whether the persistently infected IL-10-producing phagocytes in the mesenteric lymph nodes also stimulate bursts of proliferation by Th1 memory cells that periodically circulate through this site to maintain a stable and functional protective population. Accomplishing our specific aims with a robust defined in vivo model system could guide vaccine development against this recalcitrant class of pathogens.