Identifying novel regulatory pathways underlying T helper 1 cell immune responses

项目总结 在免疫反应过程中，CD4T辅助细胞识别入侵的病原体，增殖，并 分泌细胞因子以帮助免疫介导的感染清除。这将导致初始扩展 感染高峰期的效应者CD4T细胞。这些细胞包括效应器T辅助细胞1(TH1)，它介导 对细胞内病原体的免疫反应。当病原体被消除时，效应细胞群是 减少，但长寿记忆T细胞的子集能够更快地响应和 对反复接触病原体的反应很强烈。此效应器到内存的转换是 产生自然发生的长期免疫和疫苗诱导的免疫。 除了它们对记忆细胞库的贡献外，一项新兴的文献表明，TH1 细胞也可能通过与T滤泡辅助细胞(TFH)共享的可塑性参与体液免疫的某些方面 子集。TFH细胞与B细胞进行同源相互作用以协助产生病原体中和 抗体。综上所述，上述发现表明，TH1细胞能够经历阶段特异性 允许对体液和记忆细胞免疫作出贡献的表型变化。然而，目前， 关于这些关键的细胞转变发生的分子机制，知识上存在差距。 BCL-6是一种转录抑制因子，对TFH和中枢记忆T细胞的分化都是必需的。 最近，我们已经证明，TH1细胞上调依赖于Bcl6的TFH和中医样蛋白的表达 抗原刺激和IL-2信号转导减弱。有趣的是，这些细胞还共同表达IL-6Rα和IL-7R， 支持TFH和中医分化的细胞因子受体(“IL-6RαIL-7R细胞”)。重要的是，我们的 初步数据表明，随后暴露于IL-6或IL-7对TFH和中医基因的调节不同 IL-6RαIL-7R细胞。因此，我们假设IL-6和IL-7依赖于转录的改变 Th1来源的IL-6RαIL-7R细胞的景观允许它们对体液和记忆细胞反应做出贡献。 为了验证这一假设，我们将1)确定IL-6依赖对IL-6RαIL-6表型和功能的影响 7R细胞，2)评估IL-7依赖对IL-6RαIL-7R细胞表型和功能的影响，以及 3)体内评价IL-6R、α、IL-7R细胞对免疫应答的功能贡献。 从这些研究中获得的发现将是重要的，因为它们将为 支持TH1细胞在体液和记忆中所扮演角色的分子机制 回应。这样，我们的工作将为小说的设计提供分子构建块 免疫治疗策略和日益有效的疫苗。

PROJECT SUMMARY During the course of an immune response, CD4+ T helper cells identify invading pathogens, proliferate, and  secrete cytokines to aid in immune-mediated clearance of infection. This results in an initial expansion of effector CD4+ T cells at the peak of infection. These include effector T helper 1 (TH1) cells, which mediate immune responses to intracellular pathogens. As pathogen is eliminated, the effector cell population is reduced, with the exception of a subset of long-lived memory T cells capable of responding more quickly and robustly to a repeated encounter with the pathogen. This effector-to-memory transition is required for the generation of both naturally occurring long-term and vaccine-induced immunity. In addition to their contribution to the memory cell pool, an emerging body of literature suggests that TH1 cells may also engage in aspects of humoral immunity via plasticity shared with the T follicular helper (TFH) cell subset. TFH cells engage in cognate interactions with B cells to assist in the production of pathogen-neutralizing antibodies. Taken together, the above findings suggest that TH1 cells are capable of undergoing stage-specific phenotypic changes that allow for contributions to humoral and memory cell immunity. Currently, however, gaps in knowledge exist regarding the molecular mechanisms by which these critical cellular transitions occur. Bcl-6 is a transcriptional repressor required for both TFH and central memory T (TCM) cell differentiation. Recently, we demonstrated that TH1 cells up-regulate Bcl-6-dependent TFH- and TCM-like profiles in response to diminished antigen stimulation and IL-2 signaling. Intriguingly, these cells also co-express IL-6Rα and IL-7R, cytokine receptors that support TFH and TCM differentiation, respectively (“IL-6Rα+IL-7R+ cells”). Importantly, our preliminary data indicate that subsequent exposure to IL-6 or IL-7 differentially regulates TFH and TCM genes in IL-6Rα+IL-7R+ cells. Therefore, we hypothesize that IL-6- and IL-7-dependent alterations to the transcriptional landscape of TH1-derived IL-6Rα+IL-7R+ cells allow them to contribute to humoral and memory cell responses. To test this hypothesis we will 1) determine the IL-6-dependent effects on phenotype and function of IL-6Rα+IL- 7R+ cells, 2) assess the IL-7-dependent effects on phenotype and function of IL-6Rα+IL-7R+ cells, and 3) assess the functional contribution of IL-6Rα+IL-7R+ cells to immune responses in vivo. The findings obtained from these studies will be significant, as they will provide novel insight into the molecular mechanisms that support previously unappreciated roles for TH1 cells in humoral and memory responses. In doing so, our work will provide the molecular building blocks for the design of novel immunotherapeutic strategies and increasingly effective vaccines.