Mucosal-Pull Induction of Lung-Resident Memory CD8 T Cells in Parenteral TB Vaccine-Primed Hosts Requires Cognate Antigens and CD4 T Cells

Tissue-resident memory T cells (T_RM) are critical to host defense at mucosal tissue sites. However, the parenteral route of immunization as the most commonly used immunization route in practice is not effective in inducing mucosal T_RM cells particularly in the lung. While various respiratory mucosal (RM)-pull strategies are exploited to mobilize parenteral vaccine-primed T cells into the lung, whether such RM-pull strategies can all or differentially induce Ag-specific T_RM cells in the lung remains unclear. Here, we have addressed this issue by using a parenteral TB vaccine-primed and RM-pull model. We show that both Ag-independent and Ag-dependent RM-pull strategies are able to mobilize Ag-specific CD8 T cells into the lung. However, only the RM-pull strategy with cognate antigens can induce robust Ag-specific CD8 T_RM cells in the lung. We also show that the cognate Ag-based RM-pull strategy is the most effective in inducing T_RM cells when carried out during the memory phase, as opposed to the effector phase, of T cell responses to parenteral prime vaccination. We further find that cognate Ag-induced CD4 T cells play an important role in the development of CD8 T_RM cells in the lung. Our study holds implications in developing effective vaccine strategies against respiratory pathogens.