| Help provided by CD4 T lymphocytes is known to be required for the priming and maintenance of cytotoxic CD8 T lymphocytes (CTLs) during a primary infection. However, little is known about the contribution of CD4 T cell help (T H) to either the primary CD8 T cell response during Listeria monocytogenes infection or to the recall response mounted by memory CD8 T cells against secondary infection. Therefore, we began this investigation by first examining the role of CD4 T cells during a primary L. monocytogenes infection. We next analyzed the role of TH in the generation of antigen (Ag)-specific CD8 T cell memory by utilizing a heterologous prime-boost strategy which enabled the evaluation of Ag-specific recall responses. While we discovered that the primary CD8 T cell response during L. monocytogenes infection did not require CD4 T cells, we observed qualitative differences in memory CD8 T cells generated in the absence of CD4 T cells. Upon secondary stimulation, these memory CD8 T cells were impaired in their ability to produce large amounts of effector cytokines, proliferate, and provide in vivo protection against pathogenic challenge. Thus, we found that T H during the primary immune response to infection, and not during the recall response, was critical for generation of functional CD8 T memory cells. We further dissected the contribution by CD4 T cells to memory CD8 T cells by investigating the roles of CD40L and CD28, two important molecular costimulation pathways stimulated by activated CD4 T cells for the regulation of immune responses. Both of these pathways were found to be critical for the generation of CD8 T cell memory capable of robust recall responses, which demonstrates their functional significance in the mechanism by which CD4 T cells regulate CD8 T cell responses to infection. In summary, we have characterized the dispensable role for CD4 T cells in primary CD8 T cell responses during acute L. monocytogenes infection and have furthermore identified a novel role for TH, which is predominantly via CD40L-CD40 molecular costimulation during priming, for the generation of functional memory CD8 T cells. |
