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

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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.