Protective CD4+ T cells

描述（由申请人提供）：CD4+ T细胞通过调节B细胞、CD8+ T细胞和吞噬细胞的功能，在细胞内和细胞外微生物的适应性免疫应答中发挥重要作用。然而，在CD4+ T细胞缺陷的艾滋病患者中，由分枝杆菌、沙门氏菌和隐球菌引起的吞噬体感染的流行表明，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没有针对这些每年夺去200万人生命的病原体的有效疫苗。当考虑到CD4+ T细胞依赖性“伴随免疫”的奇怪特征时，这种知识差距的大小就变得清晰起来，这可能对所有吞噬体感染都起作用。产生IFN-γ的Th1细胞在感染的初始部位控制吞噬细胞内的感染，并防止其扩散到身体的其他部位。然而，奇怪的是，Th1细胞从未将微生物从初始位置清除。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消除来自身体其他部位的细菌。允许Th1细胞控制感染而不消除感染的调节机制尚不清楚。此外，为什么CD4+ T细胞记忆在原始感染被消除后不会被保留，以及为什么持续感染不会导致T细胞耗竭，目前尚不清楚。我们将使用一种基于敏感肽：主要组织相容性复合体II （p:MHCII）四聚体的细胞富集方法来研究内源性CD4+ T细胞对由摄入肠沙门氏菌血清型鼠伤寒（ST）细菌引起的典型持续性吞噬体感染的反应，以深入了解保护性CD4+ T细胞是如何产生和功能的。我们将测试我们的想法，即p: MHCII复合物仅由感染的吞噬细胞呈递，驱动产生IFN-γ- Th1效应细胞，而不产生B细胞依赖性滤泡辅助性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，在这种状态下，它们保留了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的吞噬细胞是否也刺激Th1记忆细胞的增殖爆发，Th1记忆细胞周期性地在该部位循环，以维持稳定和功能性的保护细胞群。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性病原体的疫苗开发。

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.