Abstract
Tissue-resident memory T cells (TRM) 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 TRM 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 TRM 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 TRM cells in the lung. We also show that the cognate Ag-based RM-pull strategy is the most effective in inducing TRM 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 TRM cells in the lung. Our study holds implications in developing effective vaccine strategies against respiratory pathogens.
Highlights
Pulmonary tuberculosis (TB) remains to be a leading single infectious threat to the global health [1]
It is known that parenteral-prime immunization alone is unable to induce bona fide M.tb Ag85A tetramer (Ag)-specific T cell responses in the lung but Ag-independent and -dependent respiratory mucosal (RM)-pull strategies can be employed to recruit systemically activated Ag-specific CD8 T cells to the lung [14, 19, 20, 22]
The T cells located in lung parenchymal tissue (LPT) and those in lung vasculature (LV) were differentiated by intravascular staining throughout this study [15, 30] (Supplementary Figure 1)
Summary
Pulmonary tuberculosis (TB) remains to be a leading single infectious threat to the global health [1]. The only licensed TB vaccine Bacille Calmette-Guérin (BCG) has been administered via the skin to humans for more than six decades but it has failed to effectively control global TB epidemics. The past decade has seen more than a dozen new vaccine candidates entering various phases of clinical trials, which were developed to boost or replace BCG [2, 3]. Most of these vaccine candidates were designed for the parenteral route of application based on its safety, convenience, low cost, and ease of integrating into the current human immunization program. The parenteral route is most widely and practically used in successful human immunization program. The parenteral route of TB vaccination is much less effective when compared
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