Control of Humoral and Cellular Immunity to Viral Infections of the Lung by Follicular CD8 T Cells

对肺部病毒感染的免疫需要免疫的体液和细胞手臂之间的合作 系统。一个新定义的CD8T细胞亚群，称为CXCR5+CD8T细胞，已经被发现。CXCR5+CD8 T细胞可以进入淋巴结的B细胞滤泡，并与B细胞相互作用。在慢性疾病的背景下 感染这些CXCR5+CD8 T细胞可能具有干细胞样潜能，并可以进一步分化为效应器CD8 T细胞。因此，CXCR5+CD8 T细胞可能具有独特的多功能来控制体液和细胞。 免疫系统的手臂。然而，对CXCR5+CD8 T细胞功能的基本了解 由于缺乏在体内研究这些细胞的工具。拟议研究的目的是澄清 CXCR5+CD8 T细胞在调节细胞和抗体介导的抗病毒免疫中的确切作用 评估控制这些功能的内在和外在机制。我们 假设多功能CXCR5+CD8 T细胞抑制体液免疫，但对细胞免疫是必要的 免疫力和T细胞记忆。我们还假设免疫系统可以通过改变 CXCR5+CD8T细胞通过来自效应TFH细胞的外在信号和内在因素，如 转录因子Tbet的表达。为了验证这些假设，我们将：1)评估CXCR5+的作用 CD8T细胞在病毒感染和疫苗接种过程中不同时间对体液免疫和细胞免疫的调控作用 流感和SARS-CoV-2，以及2)评估来自TFH细胞的外部信号和内部信号的作用 从Tbet到控制CXCR5+CD8 T细胞存储和多功能。我们将通过以下方式实现这些目标 病毒感染期间体内识别和干扰CXCR5+CD8 T细胞亚群的创新策略 在完整的多克隆小鼠中接种疫苗。这些策略包括新开发的CXCR5+CD8 T细胞删除器 和TFH细胞延迟模型，便于评估病毒不同阶段的功能 感染和接种疫苗。这些研究的预期结果是阐明， 及其调控机制，CXCR5+CD8 T细胞对体液免疫和细胞免疫的调节。这些研究 是重要的，因为它们将导致对免疫系统如何介导抗病毒的更深层次的理解 并将为开发新的治疗方法提供框架，以增强抗病毒免疫力和 提高对流感和SARS-CoV-2的疫苗效力。

Immunity to viral infections of the lung require cooperation between humoral and cellular arms of the immune system. A newly defined subset of CD8 T cell, called CXCR5+ CD8 T cells, have been identified. CXCR5+ CD8 T cells can gain access to the B cell follicle of lymph nodes and interact with B cells. In settings of chronic infection these CXCR5+ CD8 T cells may have stem-like potential and can differentiate further into effector CD8 T cells. Therefore, CXCR5+ CD8 T cells may have unique polyfunctionality to control both humoral and cellular arms of the immune system. However, a fundamental understanding of the functions of CXCR5+ CD8 T cells is lacking due to a paucity of tools to study these cells in vivo. The object of the proposed studies is to elucidate the precise roles of CXCR5+ CD8 T cells in regulating cellular and antibody mediated anti-viral immunity during acute respiratory infections, and to assess intrinsic and extrinsic mechanisms controlling these functions. We hypothesize that polyfunctional CXCR5+ CD8 T cells restrain humoral immunity yet are essential for cellular immunity and T cell memory. We also hypothesize that the immune system can fine-tune immunity by altering CXCR5+ CD8 T cell fates through extrinsic signals from effector Tfh cells, and intrinsic factors such as the expression of the transcription factor Tbet. To test these hypotheses, we will: 1) assess the roles of CXCR5+ CD8 T cells to control humoral and cellular immunity at distinct times in vivo during viral infection and vaccination with Influenza and SARS-CoV-2, and 2) assess the roles of extrinsic signals from Tfh cells and intrinsic signals from Tbet to control CXCR5+ CD8 T cell memory and polyfunctionality. We will pursue these aims using innovative strategies to identify and perturb CXCR5+ CD8 T cell subsets in vivo during viral infection and vaccination in intact, polyclonal, mice. These strategies include newly developed CXCR5+ CD8 T cell deleter and Tfh cell deleter models which facilitate the assessment of functionality during the distinct stages of viral infection and vaccination. The expected outcome of these studies is an elucidation of the precise functions of, and mechanisms controlling, CXCR5+ CD8 T cell regulation of humoral and cellular immunity. These studies are significant because they will lead to a deeper understanding of how the immune system mediates anti-viral immunity and will provide framework for the development of new therapeutics to enhance anti-viral immunity and promote vaccine efficacy to influenza and SARS-CoV-2.