TY - JOUR

T1 - Mucosal boosting of H56:CAF01 immunization promotes lung-localized T cells and an accelerated pulmonary response to Mycobacterium tuberculosis infection without enhancing vaccine protection

AU - Woodworth, Joshua S.

AU - Christensen, Dennis

AU - Cassidy, Joseph P.

AU - Agger, Else Marie

AU - Mortensen, Rasmus

AU - Andersen, Peter

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

U2 - 10.1038/s41385-019-0145-5

DO - 10.1038/s41385-019-0145-5

M3 - Journal article

C2 - 30760832

AN - SCOPUS:85061480252

VL - 12

SP - 816

EP - 826

JO - Mucosal Immunology

JF - Mucosal Immunology

SN - 1933-0219

IS - 3

ER -