The immune mechanisms underlying unsatisfactory pulmonary mucosal protection by parenteral Bacillus Calmette-Guérin (BCG) immunization remain poorly understood. We found that parenteral BCG immunization failed to elicit airway luminal T cells (ALT) whereas it induced significant T cells in the lung interstitium. After Mycobacterium tuberculosis (M.tb) challenge, ALT remained missing for 10 days. The lack of ALT correlated with lack of lung protection for 14 days post-M.tb challenge. To further investigate the role of ALT, ALT were elicited in BCG-immunized animals by intranasal inoculation of M.tb culture-filtrate (CF) proteins. Installment of ALT by CF restored protection in the early phases of M.tb infection, which was linked to rapid increases in ALT, but not in lung interstitial T cells. Also, adoptive transfer of T cells to the airway lumen of BCG-immunized animals also accelerated protection. This study thus provides novel evidence that unsatisfactory lung protection by parenteral BCG immunization is due to delayed ALT recruitment after pulmonary M.tb exposure.

Mycobacterium tuberculosis(M.tb), the causative bacterium of pulmonary tuberculosis (TB), is a serious global health concern. Central toM.tbeffective immune avoidance is its ability to modulate the early innate inflammatory response and prevent the establishment of adaptive T-cell immunity for nearly three weeks. When compared with other intracellular bacterial lung pathogens, such asLegionella pneumophila, or even closely related mycobacterial species such asM. smegmatis, this delay is astonishing. Customarily, the alveolar macrophage (AM) acts as a sentinel, detecting and alerting surrounding cells to the presence of an invader. However, in the case ofM.tb,this may be impaired, thus delaying the recruitment of antigen-presenting cells (APCs) to the lung. Upon uptake by APC populations,M.tbis able to subvert and delay the processing of antigen, MHC class II loading, and the priming of effector T cell populations. This delay ultimately results in the deferred recruitment of effector T cells to not only the lung interstitium but also the airway lumen. Therefore, it is of upmost importance to dissect the mechanisms that contribute to the delayed onset of immune responses followingM.tbinfection. Such knowledge will help design the most effective vaccination strategies against pulmonary TB.

Interaction of mycobacteria with the host leads to retarded expression of T helper cell type 1 (Th1) immunity in the lung. However, the immune mechanisms remain poorly understood. Using in vivo and in vitro models of Mycobacterium tuberculosis (M. tb) infection, we find the immunoadaptor DAP12 (DNAX-activating protein of 12 kDa) in antigen-presenting cells (APCs) to be critically involved in this process. Upon infection of APCs, DAP12 is required for IRAK-M (interleukin-1 receptor-associated kinase M) expression, which in turn induces interleukin-10 (IL-10) and an immune-suppressed phenotype of APCs, thus leading to suppressed Th1 cell activation. Lack of DAP12 reduces APC IL-10 production and increases their Th1 cell-activating capability, resulting in expedited Th1 responses and enhanced protection. On the other hand, adoptively transferred DAP12-competent APCs suppress Th1 cell activation within DAP12-deficient hosts, and blockade of IL-10 aborts the ability of DAP12-competent APCs to suppress Th1 activation. Our study identifies the DAP12/IRAK-M/IL-10 to be a novel molecular pathway in APCs exploited by mycobacterial pathogens, allowing infection a foothold in the lung.