Mucosal boosting of H56:CAF01 immunization promotes lung-localized T cells and an accelerated pulmonary response to Mycobacterium tuberculosis infection without enhancing vaccine protection.

T cell-mediated protection against Mycobacterium tuberculosis (Mtb) is dependent upon the ability to localize within the site of pulmonary infection and directly interact with infected cells. In turn, vaccine strategies to improve rapid T cell targeting of Mtb-infected cells after pulmonary exposure are being actively pursued. Given parenterally, the subunit vaccine H56:CAF01 elicits polyfunctional CD4 T cells that localize to the lung parenchyma and confer durable protection. Here, we find that airway mucosal boosting of parenteral H56:CAF01 immunization greatly enhances the population of long-lived lung-resident T cells (Trm) and increases early vaccine T cell responses to pulmonary Mtb challenge in multiple mouse models. However, mucosal boosting does not alter the Th1/17 vaccine signature typical of H56:CAF01 and does not further improve durable control of pulmonary infection following aerosol Mtb-challenge. Additional mucosal boosting with H56:CAF01 further enhances the Trm response without further improving protection, while blocking the recruitment of non-Trm with FTY720-treatment failed to exposed Trm-mediated protection in mucosally boosting animals. These results demonstrate the limitations of maximizing lung-localized Trm in vaccine control of pulmonary Mtb infection, especially within an immunization protocol that is already optimized for the induction of mucosal-homing Th17 cells.