Stem-like CD8 T Cells are Essential for Cellular Immunity but Restrain Antibody Responses During Influenza Infection

Abstract

Stem-like CD8+ T cells have important roles in supplying effector CD8+ T cells during chronic antigen exposure such as in chronic infection and cancer. Stem-like CD8+ T cells express the chemokine receptor CXCR5 and may also gain access to B cell follicles. However, the precise roles of stem-like CD8+ T cells in mediating cellular and humoral immunity in settings of acute infection are relatively unknown due to a lack of tools. Here I developed a mouse model to delete CXCR5 expressing stem-like CD8+ T cells and used this model to assess the roles of these cells during acute influenza infection. First, I assessed the roles of these cells in cellular immunity. I found that CXCR5+ CD8+ T cells generated in influenza infection transcriptionally resemble CXCR5+ CD8+ T cells from chronic settings as well as follicular helper T (Tfh) cells. Deletion of CXCR5+ CD8+ T cells resulted in a loss of antigen-specific CD8+ effector T cells in lymph nodes and lungs leading to the inability to control influenza infection. I also found that CXCR5+ CD8+ T cells were required for full immunity after heterologous influenza infection, but not for memory CD8+ T cell expansion. Not all CXCR5+ CD8+ T cells possessed the same functionality, as Tbet+CXCR5+CD8+ T cells did not contribute substantially to cellular immunity. Secondly, I assessed the role of stem-like CD8+ T cells in humoral immunity. I found that CXCR5+ CD8+ T cells inhibited humoral immunity during acute influenza infection. Deletion of CXCR5+ CD8+ T cells in vaccine boosting models resulted in increased antibody responses but reduced clonal expansion of germinal center B cells. Thus, my studies uncover the multiple functions of stem-like CD8+ T cells during acute infection and vaccination. Taken together, the studies presented here not only provide insights into the early contribution of stem-like CD8+ T cells to controlling acute lung infections through the generation of effector CD8+ T cells, but also demonstrate how stem-like CD8+ T cells control B cell responses in the course of an acute viral infection and vaccination.