Airway Delivery of Soluble Mycobacterial Antigens Restores Protective Mucosal Immunity by Single Intramuscular Plasmid DNA Tuberculosis Vaccination: Role of Proinflammatory Signals in the Lung

Abstract

Protection by parenteral immunization with plasmid DNA vaccines against pulmonary tuberculosis (TB) is very modest. In this study, we have investigated the underlying mechanisms for the poor mucosal protective efficacy and the avenues and mechanisms to improve the efficacy of a single i.m. immunization with a monogenic plasmid DNA TB vaccine in a murine model. We show that i.m. DNA immunization fails to elicit accumulation of Ag-specific T cells in the airway lumen despite robust T cell responses in the spleen. Such systemically activated T cells cannot be rapidly mobilized into the airway lumen upon Mycobacterium tuberculosis exposure. However, airway deposition of low doses of soluble mycobacterial Ags in previously immunized mice effectively mobilizes the systemically activated T cells into the airway lumen. A fraction of such airway luminal T cells can persist in the airway lumen, undergo quick, robust expansion and activation and provide marked immune protection upon airway M. tuberculosis exposure. Airway mucosal deposition of soluble mycobacterial Ags was found to create a tissue microenvironment rich in proinflammatory molecules including chemokines and hence conducive to T cell recruitment. Thus, in vivo neutralization of MIP-1α or IFN-inducible protein-10 markedly inhibited the accumulation of Ag-specific T cells in the airway lumen. Our data suggest that immunoprotective efficacy on the mucosal surface by i.m. plasmid DNA immunization could be substantially improved by simple mucosal soluble Ag inoculation and restoration of mucosal luminal T cells. Our study holds implication for the future design of DNA vaccination strategies against intracellular infections.

Importance of T-cell location rekindled: implication for tuberculosis vaccination strategies

“…Experimental studies using genetic or genetically modified cellbased TB vaccines have provided compelling evidence that a robust level of anti-TB protection in the lung is always correlated with the presence of antigen-specific T cells within the airway lumen [24][25][26][27]. And if such T cells are only present in the lung interstitium, spleen and circulation, even when in large quantities, the vaccinated host is poorly protected from pulmonary M. tuberculosis challenge.…”

“…Indeed, in most instances of parenteral vaccination, the magnitude of lung interstitial T-cell responses often mirrors that of the spleen [24][25][26][27]. However, the lung can be divided into two compartments: the airway lumen and lung interstitium.…”

“…While the results from aforementioned studies promote the notion of respiratory mucosal TB immunization, they provide an important immunologic clue to developing much needed novel strategies for improving the protective efficacy of parenteral immunization [17,24,[27][28][29][30]. Such new strategies will aim to mobilize the systemically located antigen-specific T cells activated by parenteral immunization into the airway lumen and subsequently sustain them.…”

“…Such new strategies will aim to mobilize the systemically located antigen-specific T cells activated by parenteral immunization into the airway lumen and subsequently sustain them. The most effective and innocuous way is perhaps to inoculate purified soluble M. tuberculosis proteins to the airway of parenterally immunized hosts [24,27]. Such proteins must be those expressed by the parenteral TB vaccine, either a genetic-based or BCG vaccine.…”

“…Thus, the lack of airway luminal T cells may explain why parenteral immunization with plasmid DNA, virus-vectored or cell-based TB vaccine is poorly protective [10,15,17,24,26,27]. By contrast, a single respiratory mucosal inoculation of virus-vectored or cell-based TB vaccine induces a strong presence of antigen-specific memory T cells within the airway lumen and provides robust protection from pulmonary M. tuberculosis challenge [24][25][26][27]. The maintenance of, and protection by, airway luminal CD8 T cells can be independent of systemic T-cell recruitment [Jeyanathan M et al, Unpublished Data].…”