Host immune response in tuberculosis: An examination of the interaction of Mycobacterium tuberculosis with dendritic cells and macrophages

Tuberculosis is a pulmonary infectious disease caused by Mycobacterium tuberculosis. Cell-mediated immune responses are protective in tuberculosis, and production of cytokines by macrophages and dendritic cells is crucial for initiating cellular immune responses to M. tuberculosis . The effects of microbial stimuli on dendritic cells and macrophages are mediated through Toll-like receptors (TLRs) that recognize specific patterns of microbial components. In this study we therefore first examined the dependency on TLR2 and TLR4 for M. tuberculosis induced cytokine production by dendritic cells and macrophages.; Our studies demonstrated that M. tuberculosis-induced TNF, IL-6, and IL-10 production from dendritic cells is largely dependent on TLR2 signaling. In contrast, absence of TLR4 did not alter these cytokine profiles. An important inference from our studies was M. tuberculosis -induced IL-12 production, maturation and Th1 polarizing capacity of dendritic cells were not affected in the absence of TLR2 or TLR4, suggesting redundancy between TLR2 and TLR4, or possibly involvement of other receptors in IL-12 production and maturation. In response to M. tuberculosis infection, macrophages exhibited differences in their dependency on TLR2 and TLR4 for cytokine production. IL-10, TNF and IL-6 from macrophages was predominantly dependent on TLR2 signaling. As expected, the level of IL-12 from wild-type infected macrophages was very low. Interestingly this low production was further impaired in the absence of TLR2 signaling. In the absence TLR4 signaling, TNF and IL-6 production was partially reduced. These differences in dependency on cytokine production from both cell types may be due to their distinct roles in the immune response.; Since dendritic cells and macrophages displayed differential responses when infected with M. tuberculosis, we next examined global gene transcription from both cells by employing the microarray technology. Analysis of microarray data revealed that dendritic cells modulated the expression of genes preferentially involved in initiating cellular immunity whereas macrophages regulated the expression of genes preferentially involved in the growth of intracellular M. tuberculosis. The microarray studies provide a framework for future studies that will directly test in murine models of M. tuberculosis infection how the characteristic transcriptional profiles of the two cell types impact on disease modulation.