Mucosal BCG Vaccination Induces Protective Lung-Resident Memory T Cell Populations against Tuberculosis

Abstract

Mycobacterium bovis Bacille Calmette-Guérin (BCG) is the only licensed vaccine against tuberculosis (TB), yet its moderate efficacy against pulmonary TB calls for improved vaccination strategies. Mucosal BCG vaccination generates superior protection against TB in animal models; however, the mechanisms of protection remain elusive. Tissue-resident memory T (TRM) cells have been implicated in protective immune responses against viral infections, but the role of TRM cells following mycobacterial infection is unknown. Using a mouse model of TB, we compared protection and lung cellular infiltrates of parenteral and mucosal BCG vaccination. Adoptive transfer and gene expression analyses of lung airway cells were performed to determine the protective capacities and phenotypes of different memory T cell subsets. In comparison to subcutaneous vaccination, intratracheal and intranasal BCG vaccination generated T effector memory and TRM cells in the lung, as defined by surface marker phenotype. Adoptive mucosal transfer of these airway-resident memory T cells into naive mice mediated protection against TB. Whereas airway-resident memory CD4+ T cells displayed a mixture of effector and regulatory phenotype, airway-resident memory CD8+ T cells displayed prototypical TRM features. Our data demonstrate a key role for mucosal vaccination-induced airway-resident T cells in the host defense against pulmonary TB. These results have direct implications for the design of refined vaccination strategies.

The generation of T‐cell memory to protect against tuberculosis

“…Lymphocytes resident in the lung are sufficient for BCG‐induced protection of mice against M. tuberculosis infection, as blocking egress of cells from the secondary lymphoid organs did not alter the protective effect of the vaccine . Mucosal delivery of BCG in multiple animal models has shown an improvement in protective efficacy compared with parenteral delivery although intriguingly earlier studies showed no difference between vaccination routes . The reason for this difference is unclear but may relate to use of antibiotics to clear bacterial load after immunization in the Palendira study, as it was subsequently identified that vaccine persistence and BCG antigen load impacts T‐cell immunity .…”

Integrating Lung Physiology, Immunology, and Tuberculosis

“…Given its primary function, inhaled microbes represent a particular challenge, especially host-adapted pathogens like M.tb that have evolved to enter and survive following their entry in the lung where they can get an upper hand early in their pathogenesis. On the other hand, lungs also have uniquely effective clearance capabilities, including rapid recruitment of lymphocytes to the airways and the existence of tissue-resident memory T cells within the lung [88]. Herein we describe several IPs for M.tb as it transits the lung and point out how little we know about these interactions.…”

Development of tuberculosis vaccines in clinical trials: Current status

“…In addition, these vaccines are expected to elicit an abundant and longer immune response in humans that can induce superior protection against all forms of the disease . Furthermore, it has recently been demonstrated that mucosal or intravenous vaccination with whole‐cell TB vaccines induces a better protection than parenteral vaccination …”