Identifying novel regulatory pathways underlying T helper 1 cell immune responses

识别 T 辅助细胞 1 细胞免疫反应的新调控途径

• 批准号: 10001826
• 负责人: Kenneth Joseph Oestreich
• 金额: $ 22.49万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-23 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001826
• 关键词: Identifying; novel; regulatory; pathways; underlying

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.

项目摘要 在免疫应答过程中，CD 4 + T辅助细胞识别入侵的病原体，增殖， 分泌细胞因子以帮助免疫介导的感染清除。这导致初始膨胀， 在感染高峰期的效应CD 4 + T细胞。这些包括效应T辅助1（TH 1）细胞，其介导 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 减少，除了能够更快地响应的长寿记忆T细胞的子集， 与病原体的反复接触有关这种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之外，一个新兴的文献表明，TH 1 细胞也可以通过与T滤泡辅助细胞（TFH）共享的可塑性参与体液免疫的各个方面 子集TFH细胞参与与B细胞的同源相互作用，以帮助产生病原体中和性免疫应答。 抗体的综上所述，上述发现表明，TH 1细胞能够经历阶段特异性的免疫调节。 表型变化，允许体液和记忆细胞免疫的贡献。然而，目前， 关于这些关键细胞转变发生的分子机制存在知识空白。 Bcl-6是TFH和中央记忆T（TCM）细胞分化所需的转录抑制因子。 最近，我们证明了TH 1细胞上调Bcl-6依赖的TFH和TCM样谱， 减少抗原刺激和IL-2信号传导。有趣的是，这些细胞还共表达IL-6 R α和IL-7 R， 分别支持TFH和TCM分化的细胞因子受体（“IL-6 R α+IL-7 R+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可不同程度地调节TFH和TCM基因， IL-6 R α+IL-7 R+细胞。因此，我们假设IL-6和IL-7依赖性的转录水平的改变， TH 1衍生的IL-6 R α+IL-7 R+细胞的景观使它们有助于体液和记忆细胞应答。 为了验证这一假设，我们将1）确定IL-6依赖性对IL-6 R α+IL-6细胞表型和功能的影响。 2）评估IL-7依赖性对IL-6 R α+IL-7 R+细胞的表型和功能的影响，以及 3)评估IL-6 R α+IL-7 R+细胞对体内免疫应答的功能贡献。 从这些研究中获得的结果将是重要的，因为它们将为我们提供新的见解。 支持TH 1细胞在体液和记忆中以前未被认识的作用的分子机制 应答在这样做的过程中，我们的工作将为设计新的 免疫策略和越来越有效的疫苗。