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臂之间的合作。 系统已经鉴定了一种新定义的CD 8 T细胞亚群，称为CXCR 5 + CD 8 T细胞。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。在慢性疾病的环境中， 这些CXCR 5 + CD 8 T细胞可能具有干细胞样潜能，并可进一步分化为效应CD 8 + T细胞。 T细胞。因此，CXCR 5 + CD 8 T细胞可能具有独特的多功能性，以控制体液和细胞免疫。 免疫系统的武器。然而，对CXCR 5 + CD 8 T细胞功能的基本理解 由于缺乏在体内研究这些细胞的工具，拟议研究的目的是阐明 CXCR 5 + CD 8 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， 急性呼吸道感染，并评估控制这些功能的内在和外在机制。我们 假设多功能CXCR 5 + CD 8 T细胞抑制体液免疫，但对于细胞免疫是必需 免疫和T细胞记忆。我们还假设，免疫系统可以通过改变免疫系统的功能来微调免疫力。 CXCR 5 + CD 8 T细胞命运通过来自效应Tfh细胞的外在信号和内在因素，如免疫调节因子。 转录因子Tbet的表达。为了验证这些假设，我们将：1）评估CXCR 5+的作用 在病毒感染和疫苗接种期间在体内不同时间控制体液和细胞免疫的CD 8 T细胞 与流感和SARS-CoV-2，和2）评估来自Tfh细胞的外在信号和内在信号的作用 从Tbet控制CXCR 5 + CD 8 T细胞记忆和多功能性。我们将通过以下方式实现这些目标： 在病毒感染期间体内鉴定和干扰CXCR 5 + CD 8 T细胞亚群的创新策略， 在完整的多克隆小鼠中接种。这些策略包括新开发的CXCR 5 + CD 8 T细胞删除器 和Tfh细胞删除模型，其有助于评估病毒感染的不同阶段期间的功能 感染和疫苗。这些研究的预期结果是阐明以下物质的确切功能， 和机制控制，CXCR 5 + CD 8 T细胞调节体液和细胞免疫。这些研究 是重要的，因为它们将导致更深入地了解免疫系统如何介导抗病毒 并将为开发新的治疗方法提供框架，以增强抗病毒免疫力， 提高疫苗对流感和SARS-CoV-2的效力。

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.