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PPE38 Protein of Mycobacterium tuberculosis Inhibits Macrophage MHC Class I Expression and Dampens CD8+ T Cell
Lu Meng1, Jingfeng Tong1, Hui Wang2
1Key laboratory of Medical Molecular Virology, Institute of Biomedical Sciences and Institute of Medical Microbiology, Shanghai Medical College, Fudan University Shanghai, China.
Abstract:
Suppression of CD8+ T cell activation is a critical mechanism used by Mycobacterium tuberculosis (MTB) to escape protective host immune responses. PPE38 belongs to the unique PPE family of MTB and in our previous study, PPE38 protein was speculated to participate in manipulating macrophage MHC class I pathway. To test this hypothesis, the function of mycobacterial PPE38 protein was assessed here using macrophage and mouse infection models. Decreased amount of MHC class I was observed on the surface of macrophages infected with PPE38-expressing mycobacteria. The transcript of genes encoding MHC class I was also inhibited by PPE38. After infection of C57BL/6 mice with Mycobacterium smegmatis expressing PPE38 (Msmeg-PPE38), decreased number of CD8+ T cells was found in spleen, liver, and lungs through immunohistochemical analysis, comparing to the control strain harboring empty vector (Msmeg-V). Consistently, flow cytometry assay showed that fewer effector/memory CD8+ T cells (CD44highCD62Llow) were activated in spleen from Msmeg-PPE38 infected mice. Moreover, Msmeg-PPE38 confers a growth advantage over Msmeg-V in C57BL/6 mice, indicating an effect of PPE38 to favor mycobacterial persistence in vivo. Overall, this study shows a unique biological function of PPE38 protein to facilitate mycobacteria to escape host immunity, and provides hints for TB vaccine development.
Insights
Mycobacterium tuberculosis uses PPE38 protein to suppress CD8+ T cell activation, aiding its survival. This finding offers potential targets for developing new tuberculosis (TB) vaccines.
Area of Science:
- Immunology
- Microbiology
- Molecular Biology
Background:
- Mycobacterium tuberculosis (MTB) evades host immunity by suppressing CD8+ T cell activation.
- The MTB PPE38 protein, part of the unique PPE family, was previously hypothesized to influence macrophage MHC class I pathways.
Purpose of the Study:
- To investigate the function of the PPE38 protein in manipulating host immune responses.
- To assess PPE38's role in immune evasion and its impact on CD8+ T cell activation and mycobacterial persistence.
Main Methods:
- Utilized macrophage and mouse infection models with PPE38-expressing mycobacteria.
- Assessed MHC class I expression on macrophages and gene transcription.
- Quantified CD8+ T cell populations in spleen, liver, and lungs via immunohistochemistry and flow cytometry.
- Evaluated mycobacterial growth advantage in vivo.
Main Results:
- PPE38 expression led to decreased MHC class I on infected macrophages and inhibited MHC class I gene transcription.
- Infection with PPE38-expressing Mycobacterium smegmatis reduced CD8+ T cell numbers in multiple organs.
- Fewer effector/memory CD8+ T cells were activated in mice infected with PPE38-expressing M. smegmatis.
- PPE38 conferred a growth advantage to M. smegmatis in vivo, suggesting enhanced mycobacterial persistence.
Conclusions:
- The PPE38 protein actively suppresses CD8+ T cell activation, facilitating mycobacterial immune escape.
- PPE38 plays a role in promoting mycobacterial persistence within the host.
- These findings provide insights into potential strategies for developing novel tuberculosis vaccines.
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