This review focuses on recent progress in our understanding of Mycobacterium tuberculosis survival in macrophages, the interaction of M. tuberculosis with Toll-like receptors (TLRs) and the establishment of the link between innate and adaptive immunity, and TLRs and interferon-gamma-mediated antimicrobial pathways in macrophages. We also propose a paradigm that TLR2 signaling regulates the magnitude of the host Th1 response leading to either M. tuberculosis persistence and latent infection or replication and disease.
A major impediment to tuberculosis (TB) vaccine development is the lack of reliable correlates of immune protection or biomarkers that would predict vaccine efficacy. Gamma interferon (IFN-␥) produced by CD4 ؉ T cells and, recently, multifunctional CD4 ؉ T cells secreting IFN-␥, tumor necrosis factor (TNF), and interleukin-2 (IL-2) have been used in vaccine studies as a measurable immune parameter, reflecting activity of a vaccine and potentially predicting protection. However, accumulating experimental evidence suggests that host resistance against Mycobacterium tuberculosis infection is independent of IFN-␥ and TNF secretion from CD4 ؉ T cells. Furthermore, the booster vaccine MVA85A, despite generating a high level of multifunctional CD4؉ T cell response in the host, failed to confer enhanced protection in vaccinated subjects. These findings suggest the need for identifying reliable correlates of protection to determine the efficacy of TB vaccine candidates. This article focuses on alternative pathways that mediate M. tuberculosis control and their potential for serving as markers of protection. The review also discusses the significance of investigating the natural human immune response to M. tuberculosis to identify the correlates of protection in vaccination.
In this study, we report a new approach that allows dissection of distinct pathways regulating induction of early adaptive immunity in response to Mycobacterium tuberculosis (Mtb). We used traceable murine dendritic cells (DCs) and macrophage populations to chart their migratory pattern in response to Mtb, and found that only DCs receiving inflammatory stimuli from Mtb up-regulated their expression of CCR7 and migrated specifically to the draining lymph nodes (LNs). Furthermore, these Mtb-modulated DCs initiated a Th1 response only in the draining LNs. Taken together, these results demonstrate that Mtb-induced modulation of DCs is critical for their migration to regional LNs and ensuing T cell priming.
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