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PD-1/PD-L1 Pathway Modulates Macrophage Susceptibility to Mycobacterium tuberculosis Specific CD8+ T cell Induced
Guadalupe Verónica Suarez1, Claudia Del Carmen Melucci Ganzarain1, María Belén Vecchione1
1Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Universidad de Buenos Aires. Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Buenos Aires, Argentina.
Abstract:
CD8+T cells contribute to tuberculosis (TB) infection control by inducing death of infected macrophages. Mycobacterium tuberculosis (Mtb) infection is associated with increased PD-1/PD-L1 expression and alternative activation of macrophages. We aimed to study the role of PD-1 pathway and macrophage polarization on Mtb-specific CD8+T cell-induced macrophage death. We observed that both PD-L1 on CD14+ cells and PD-1 on CD8+T cells were highly expressed at the site of infection in pleurisy TB patients' effusion samples (PEMC). Moreover, a significant increase in CD8+T cells' Mtb-specific degranulation from TB-PEMC vs. TB-PBMC was observed, which correlated with PD-1 and PDL-1 expression. In an in vitro model, M1 macrophages were more susceptible to Mtb-specific CD8+T cells' cytotoxicity compared to M2a macrophages and involved the transfer of cytolytic effector molecules from CD8+T lymphocytes to target cells. Additionally, PD-L1 blocking significantly increased the in vitro Ag-specific CD8+T cell cytotoxicity against IFN-γ-activated macrophages but had no effect over cytotoxicity on IL-4 or IL-10-activated macrophages. Interestingly, PD-L1 blocking enhanced Mtb-specific CD8+ T cell killing of CD14+ cells from human tuberculous pleural effusion samples. Our data indicate that PD-1/PD-L1 pathway modulates antigen-specific cytotoxicity against M1 targets in-vitro and encourage the exploration of checkpoint blockade as new adjuvant for TB therapies.
Insights
Tuberculosis (TB) infection involves CD8+ T cells killing infected macrophages. The PD-1/PD-L1 pathway influences this process, suggesting checkpoint blockade could be a novel TB therapy adjuvant.
Area of Science:
- Immunology
- Cellular Biology
- Infectious Diseases
Background:
- CD8+ T cells are crucial for controlling tuberculosis (TB) by inducing macrophage death.
- Mycobacterium tuberculosis (Mtb) infection is linked to increased PD-1/PD-L1 expression and altered macrophage activation.
- The interplay between PD-1 pathway, macrophage polarization, and CD8+ T cell cytotoxicity in TB is not fully understood.
Purpose of the Study:
- To investigate the role of the PD-1 pathway and macrophage polarization in CD8+ T cell-mediated killing of Mtb-infected macrophages.
- To assess the impact of PD-L1 blockade on CD8+ T cell cytotoxicity against macrophages in TB patients.
Main Methods:
- Analysis of PD-1 and PD-L1 expression in CD8+ T cells and CD14+ cells from TB patients' pleural effusion and peripheral blood.
- In vitro co-culture experiments using M1 and M2a macrophages with Mtb-specific CD8+ T cells.
- Assessment of CD8+ T cell cytotoxicity and degranulation.
- In vitro blockade of the PD-L1 pathway.
Main Results:
- High expression of PD-1 on CD8+ T cells and PD-L1 on CD14+ cells was observed in TB pleural effusion samples.
- M1 macrophages were more susceptible to CD8+ T cell-induced death than M2a macrophages.
- PD-L1 blockade enhanced CD8+ T cell cytotoxicity against IFN-γ-activated (M1-like) macrophages and patient-derived CD14+ cells, but not IL-4 or IL-10-activated macrophages.
- Increased CD8+ T cell degranulation correlated with PD-1 and PD-L1 expression.
Conclusions:
- The PD-1/PD-L1 pathway modulates antigen-specific CD8+ T cell cytotoxicity against M1-polarized macrophages in vitro.
- PD-L1 blockade enhances CD8+ T cell killing of Mtb-infected macrophages.
- Targeting the PD-1/PD-L1 pathway could be a potential adjuvant strategy for TB therapies.
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