Characterizing the BCG induced T cell independent mechanisms for defense against Mycobacterium tuberculosis

Abstract

Abstract Mycobacterium bovis Bacille Calmette Guérin (BCG) is a potent immune stimulator that activates innate and adaptive immunity. In the C57BL/6 mouse model of tuberculosis, BCG stimulated immunity causes a significant reduction of M. tuberculosis burden after pulmonary infection. The majority of work has focused on BCG induced T cell immunity as CD4+ T cells play a significant role in protection against tuberculosis. We hypothesized that BCG also induced a T cell independent mechanism that was sufficient to significantly restrict mycobacterial growth. BCG robustly activates innate immunity and our preliminary experiments showed that BCG induced a significant reduction in colony forming units (CFU) in the lungs of mice vaccinated 7 days before pulmonary infection. Our studies indicated that although BCG was administered through subcutaneous inoculation, increased numbers of Ly6C+ monocytes were observed in the lungs within 7 days. Selective depletion also determined that neutrophils played a role in priming innate immunity. Others have identified a role for innate immunity during BCG vaccination termed trained innate immunity. However, our results suggested that at day 7 post BCG vaccination trained innate immunity did not cause the CFU reduction, as the NOD2 receptor or NK cell activation were not absolute requirements, despite being linked to trained immunity. Furthermore, in vivo killing of mycobacterium was dependent on BCG being viable and was monocyte derived, highlighting a novel mechanism. Taken together our data suggest that an early innate mechanism induced by viable BCG is responsible for reducing the mycobacterial burden and precedes trained innate immunity.