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Published on: March 16, 2018
Programmed death ligand 2 regulates arginase induction and modifies Trypanosoma cruzi survival in macrophages during
Laura R Dulgerian1, Vanina V Garrido, Cinthia C Stempin
1CIBICI-CONICET, Departamento Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
Abstract:
The programmed death ligands 1 (PD-L1) and 2 (PD-L2) that bind to programmed death 1 (PD-1) have been involved in peripheral tolerance and in the immune escape mechanisms during chronic viral infections and cancer. However, there are no reports about the role of these molecules during Trypanosoma cruzi infection. We have studied the role of PD-L1 and PD-L2 in T. cruzi infection and their importance in arginase/inducible nitric oxide synthase (iNOS) balance in the immunomodulatory properties of macrophages (Mφ). In this work, we have demonstrated that expression of the PD-1/PD-L pathway is modified during T. cruzi infection on Mφs obtained from peritoneal cavity. The Mφs from T. cruzi-infected mice suppressed T-cell proliferation and this was restored when anti-PD-1 and anti-PD-L1 antibodies were added. Nevertheless, anti-PD-L2 antibody treatment did not re-establish T-cell proliferation. PD-L2 blockade on peritoneal cells from infected mice showed an increase in arginase expression and activity and a decrease in iNOS expression and in nitric oxide (NO) production. Additionally, interleukin-10 production increased whereas interferon-γ production was reduced. As a result, this microenvironment enhanced parasite proliferation. In contrast, PD-1 and PD-L1 blockage increased iNOS expression and NO production on peritoneal Mφs from T. cruzi-infected mice. Besides, PD-L2 knockout infected mice showed an increased in parasitaemia as well as in arginase activity, and a reduction in NO production. Taken together, our results demonstrate that PD-L2 is involved in the arginase/iNOS balance during T. cruzi infection having a protective role in the immune response against the parasite.
Insights
Programmed death ligand 2 (PD-L2) plays a protective role in the immune response against Trypanosoma cruzi infection by modulating macrophage arginase/iNOS balance. Blocking PD-L2 exacerbates parasite proliferation, while PD-1/PD-L1 blockade enhances nitric oxide production.
Area of Science:
- Immunology
- Parasitology
- Molecular Biology
Background:
- Programmed death ligands (PD-L1, PD-L2) and their receptor (PD-1) are crucial for immune tolerance and immune evasion in infections and cancer.
- The role of the PD-1/PD-L pathway in Trypanosoma cruzi infection remains uncharacterized.
- Macrophages (Mφ) play a key role in regulating the immune response during T. cruzi infection.
Purpose of the Study:
- To investigate the role of PD-L1 and PD-L2 in T. cruzi infection.
- To determine the involvement of PD-L1 and PD-L2 in the arginase/inducible nitric oxide synthase (iNOS) balance in macrophages.
- To elucidate the impact of the PD-1/PD-L pathway on T-cell proliferation and parasite control.
Main Methods:
- Analysis of PD-1/PD-L pathway expression on macrophages from T. cruzi-infected mice.
- In vitro studies using anti-PD-1, anti-PD-L1, and anti-PD-L2 antibodies to assess T-cell proliferation.
- Assessment of arginase activity, nitric oxide (NO) production, and cytokine profiles (interleukin-10, interferon-γ) following antibody blockade or in PD-L2 knockout mice.
- Quantification of parasite load (parasitaemia).
Main Results:
- PD-1/PD-L pathway expression is altered on macrophages during T. cruzi infection.
- Anti-PD-1 and anti-PD-L1 antibodies restored T-cell proliferation suppressed by infected macrophages, but anti-PD-L2 did not.
- PD-L2 blockade led to increased arginase activity, decreased iNOS expression and NO production, elevated IL-10, and reduced IFN-γ, enhancing parasite proliferation.
- PD-1 and PD-L1 blockade increased iNOS expression and NO production.
- PD-L2 knockout mice exhibited increased parasitaemia, elevated arginase activity, and reduced NO production.
Conclusions:
- PD-L2 plays a critical role in maintaining the arginase/iNOS balance in macrophages during T. cruzi infection.
- PD-L2 exhibits a protective function in the immune response against T. cruzi.
- Targeting the PD-1/PD-L pathway, particularly PD-L2, may offer therapeutic strategies for Chagas disease.
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