Key Takeaways & Executive Findings
- •• Macrophage mannose receptor (MR) is essential for effective BCG vaccine-induced antimycobacterial immunity. • MR activates the JAK-STAT1 signaling pathway, upregulating MHC-II and IL-12 to enhance antigen presentation and CD4+ T cell responses. • MR deficiency in macrophages reduces BCG vaccine efficacy and increases susceptibility to M.tb challenge in mice. • These findings provide a mechanistic basis for improving BCG vaccination strategies against tuberculosis.
Abstract
Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), remains one of the leading causes of fatal infectious diseases worldwide. The only licensed vaccine, Mycobacterium bovis Bacillus Calmette-Guérin (BCG), has variable efficacy against TB in adults. Insufficiency of immune cell function diminishes the protective effects of the BCG vaccine. It is critical to clarify the mechanism underlying the antimycobacterial immune response during BCG vaccination. Macrophage mannose receptor (MR) is important for enhancing the uptake and processing of glycoconjugated antigens from pathogens for presentation to T cells, but the roles of macrophage MR in the BCG-induced immune response against M.tb are not yet clear. Here, we discover that macrophage MR deficiency impairs the antimycobacterial immune response in BCG-vaccinated mice. Mechanistically, macrophage MR triggers JAK-STAT1 signaling, which promotes antigen presentation via upregulated MHC-II and induces IL-12 production by macrophages, contributing to CD4+ T cell activation and IFN-γ production. MR deficiency in macrophages reduces the vaccine efficacy of BCG and increases susceptibility to M.tb H37Ra challenge in mice. Our results suggest that MR is critical for macrophage antigen presentation and the antimycobacterial immune response to BCG vaccination and offer valuable guidance for the preventive strategy of BCG immunization.
1. Introduction
Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), is one of the top 10 causes of death worldwide. According to a report by the World Health Organization, there were 10.6 million new cases of active TB and almost 1.3 million deaths from TB infections in 2022 [1]. The only licensed vaccine against TB, Mycobacterium bovis Bacillus Calmette-Guérin (BCG), mainly induces an IFN-γ-producing T helper type 1 (Th1) CD4+ T cell response and is effective in preventing TB among infants and children. However, the vaccine fails to confer sufficient protection against TB in adults [2,3]. Insufficient immune cell function diminishes the protective effects of the BCG vaccine. It is critical to clarify the mechanism underlying the antimycobacterial immune response during BCG vaccination.
Macrophages are crucial immune cells during the antimycobacterial immune response. Macrophages utilize pattern recognition receptors (PRRs) to directly identify a variety of pathogen-associated molecular patterns (PAMPs) of M.tb, capture bacteria, and ingest them into the phagosome. The engulfed M.tb are lysed, and bacterial proteins are degraded by proteinases in the phagolysosome, which is formed by the fusion of the phagosome and lysosome within macrophages [4]. Upon M.tb infection, macrophages also produce IL-12 and reactive oxygen species (ROS), a group of reactive molecules derived from molecular oxygen, which have direct and indirect antimicrobial immune activity [5]. Although macrophage-induced robust innate immune responses are necessary for the early clearance of M.tb infection, these cells also function as antigen-presenting cells (APCs) and present processed M.tb antigens via major histocompatibility complex (MHC) molecules for T cell activation [6].
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Ying Zhang, Dandan Xu, Qi Nie, Jing Wang, Dan Fang, Yan Xie, Huang Xiong, Qin Pan, Xiao-Lian Zhang (2026). Macrophages exploit the mannose receptor and JAK-STAT1-MHC-II pathway to drive antigen presentation and the antimycobacterial immune response after BCG vaccination. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2024100
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Frequently Asked Questions
What is the role of macrophage mannose receptor in BCG vaccination?
The macrophage mannose receptor (MR) is critical for enhancing the uptake and processing of glycoconjugated antigens from pathogens, and it drives antigen presentation and the antimycobacterial immune response after BCG vaccination by activating the JAK-STAT1-MHC-II pathway.
How does MR deficiency affect BCG vaccine efficacy?
MR deficiency in macrophages impairs the antimycobacterial immune response, reduces the vaccine efficacy of BCG, and increases susceptibility to M.tb H37Ra challenge in mice.
What signaling pathway is involved in MR-mediated antigen presentation?
MR triggers JAK-STAT1 signaling, which promotes antigen presentation via upregulated MHC-II and induces IL-12 production by macrophages, contributing to CD4+ T cell activation and IFN-γ production.
What are the implications of this study for TB vaccine development?
The findings suggest that MR is critical for macrophage antigen presentation and the antimycobacterial immune response to BCG vaccination, offering valuable guidance for improving the preventive strategy of BCG immunization.
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