It Takes a Village: The Multifaceted Immune Response to Mycobacterium tuberculosis Infection and Vaccine-Induced Immunity

Abstract

Despite co-evolving with humans for centuries and being intensely studied for decades, the immune correlates of protection against Mycobacterium tuberculosis (Mtb) have yet to be fully defined. This lapse in understanding is a major lag in the pipeline for evaluating and advancing efficacious vaccine candidates. While CD4+ T helper 1 (TH1) pro-inflammatory responses have a significant role in controlling Mtb infection, the historically narrow focus on this cell population may have eclipsed the characterization of other requisite arms of the immune system. Over the last decade, the tuberculosis (TB) research community has intentionally and intensely increased the breadth of investigation of other immune players. Here, we review mechanistic preclinical studies as well as clinical anecdotes that suggest the degree to which different cell types, such as NK cells, CD8+ T cells, γ δ T cells, and B cells, influence infection or disease prevention. Additionally, we categorically outline the observed role each major cell type plays in vaccine-induced immunity, including Mycobacterium bovis bacillus Calmette-Guérin (BCG). Novel vaccine candidates advancing through either the preclinical or clinical pipeline leverage different platforms (e.g., protein + adjuvant, vector-based, nucleic acid-based) to purposefully elicit complex immune responses, and we review those design rationales and results to date. The better we as a community understand the essential composition, magnitude, timing, and trafficking of immune responses against Mtb, the closer we are to reducing the severe disease burden and toll on human health inflicted by TB globally.

Keywords: BCG; Mycobacterium tuberculosis; immunity; infection; prevention of disease (POD); prevention of infection (POI); vaccines.

Figure 1

Immune cell subsets with critical roles during different stages of Mtb infection or generated by specific vaccine strategies. Known contributions (heatmap of light: low, dark: high, checked: mixed) of specific subsets are outlined during infection (left) or following vaccine induction (right). Macrophages, neutrophils, and B cells have known and defined contributions to controlling infection and preventing disease. Interestingly, both macrophages and neutrophils can contribute to Mtb control or serve as a niche for bacterial growth and dissemination and their dual role is highlighted (checked). Dendritic cells participate in early stages of infection and post vaccination as an APC. NK cells contribute moderately to infection control and little is known about their induction with different vaccination regimens. Antigen-specific cytolytic CD8+ T target Mtb and Mtb-infected cells, and their part in controlling latent infection, important in POD vaccination strategies, is expanding. While a multi-faceted immune response is induced to control Mtb infection, vaccine-induced immune responses essential for protection by many of these cell subsets are still understudied as endpoints. The summary presented here is a collection of information from many models and clinical data and do not reflect the data known or observed for each model (created with BioRender.com).

Figure 2

Mtb therapies focus on two main strategies, early prevention of infection or later prevention of disease. In early infection (POI, upper), detection of Mtb bacilli in the pulmonary alveoli by macrophages leads to downstream activation of innate immune cells, which may include neutrophils, NK cells, and DCs. Activated APCs can then prime T cells (CD4+ or CD8+) for further Mtb-specific adaptive responses to target Mtb and Mtb-infected cells and control infection. Novel therapies are working to skew innate immune responses to be protective and less permissive and accelerate T-cell priming and effector responses that traffic to the pulmonary space. Later stages of Mtb infection (POD, lower) and pathology are defined by formation of a granuloma, which contains Mtb by a surrounding composition of immune cells. While a hallmark of disease, there are still questions surrounding the factors that can affect granuloma formation and composition that can help resolve infection and prevent progression to active disease. Containment and POD progression seem to correlate with IgM, robust pulmonary CD4+ and CD8+ T cells, and activated inflammatory M1 macrophages and DCs at the granuloma. In contrast, regulatory TH2 CD4+ T cells, abundance of IgA or IgG4, and M2 macrophages are more associated with loss of control. Higher peripheral γδ T cells are associated with active TB disease in humans, but their direct role in granuloma control or bacterial dissemination requires further study. The balance of both the composition and magnitude of specific cellular and humoral players is becoming clearer and POD vaccine strategies will be able to benchmark these parameters in preclinical and clinical studies. The summary presented here is a collection of information from many models and clinical data and does not reflect the data known or observed for each model (created with BioRender.com).