Mucosal immunity and novel tuberculosis vaccine strategies: route of immunisation-determined T-cell homing to restricted lung mucosal compartments

Abstract

Despite the use of bacille Calmette-Guérin (BCG) for almost a century, pulmonary tuberculosis (TB) continues to be a serious global health concern. Therefore, there has been a pressing need for the development of new booster vaccines to enhance existing BCG-induced immunity. Protection following mucosal intranasal immunisation with AdHu5Ag85A is associated with the localisation of antigen-specific T-cells to the lung airway. However, parenteral intramuscular immunisation is unable to provide protection despite the apparent presence of antigen-specific T-cells in the lung interstitium. Recent advances in intravascular staining have allowed us to reassess the previously established T-cell distribution profile and its relationship with the observed differential protection. Respiratory mucosal immunisation empowers T-cells to home to both the lung interstitium and the airway lumen, whereas intramuscular immunisation-activated T-cells are largely trapped within the pulmonary vasculature, unable to populate the lung interstitium and airway. Given the mounting evidence supporting the safety and enhanced efficacy of respiratory mucosal immunisation over the traditional parenteral immunisation route, a greater effort should be made to clinically develop respiratory mucosal-deliverable TB vaccines.

FIGURE 1

Route of immunisation determines whether anti-tuberculosis (TB) T-cells acquire the ability to home to the restricted lung mucosal compartments. Protection against pulmonary TB is associated with the ability of anti-TB T-cells to exit the pulmonary vasculature and gain entry into the restricted lung mucosal compartments. a) T-cells primed within the lung local draining lymph nodes following respiratory mucosal immunisation express various lung homing molecules including α_εβ₇ (CD103), CCR1, CCR6 and α₁β₁ (VLA-1). These antigen-experienced T-cells, primed with various lung homing markers, are able to exit the pulmonary vasculature and gain entry into the lung interstitium and airway lumen. Once localised at the site of infection, these cells are able to provide rapid protection against pulmonary TB. b) T-cells primed following parenteral immunisation lack expression of lung homing molecules. Following priming in the local draining lymph nodes, these cells are restricted to the pulmonary vasculature, thus limiting their ability to provide robust anti-TB immunity.