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Programmed Cell Death Protein 1-PDL1 Interaction Prevents Heart Damage in Chronic Trypanosoma cruzi Infection
Raíssa Fonseca1, Rafael Moysés Salgado1, Henrique Borges da Silva2
1Laboratory of Immunology of Infectious Diseases, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
Insights
Blocking the PD1-PDL1 pathway in Chagas disease cardiomyopathy (CCC) models boosted T cell responses but worsened heart pathology. This suggests the PD1-PDL1 interaction protects the heart from excessive immune responses during infection.
Area of Science:
- Immunology
- Parasitology
- Cardiology
Background:
- Chagas disease affects millions, with chronic Chagas cardiomyopathy (CCC) leading to fatal heart conditions.
- In a mouse model of CCC, CD4+ and CD8+ T cells in the heart showed signs of inhibition via programmed cell death protein 1 (PD1) and PDL1.
- This suggests a potential link between PD1-PDL1 interaction, immune suppression, parasite persistence, and CCC progression.
Purpose of the Study:
- To investigate if PD1-PDL1 interaction suppresses the local immune response in the heart during chronic Chagas disease.
- To determine if blocking this interaction can restore immune function and impact CCC progression.
- To assess the combined effect of checkpoint blockade and irradiated parasite treatment on the immune response and cardiac pathology.
Main Methods:
- Treatment of chronically infected mice with anti-PD1 and anti-PDL1 blocking antibodies combined with irradiated *Trypanosoma cruzi*.
- Analysis of heart-infiltrating CD4+ and CD8+ T cells for effector memory phenotype.
- Assessment of histopathology scores, heart rate, blood parasitemia, and *T. cruzi*-specific antibody levels.
Main Results:
- Treatment increased heart-infiltrating CD4+ and CD8+ T cells with an effector memory phenotype.
- Histopathology scores increased, and heart rate decreased, indicating worsened cardiac damage.
- Blood parasitemia decreased, associated with increased *T. cruzi*-specific IgG1 antibodies, but cytokine production and parasite burden remained unchanged.
Conclusions:
- PD1-PDL1 interaction in the heart during chronic Chagas disease appears to protect against excessive immune responses.
- Blocking this pathway, while boosting T cell activity, exacerbated cardiac pathology in the murine model.
- These findings highlight a complex role of immune checkpoints in Chagas cardiomyopathy, suggesting potential risks of therapeutic intervention.
Abstract:
Chagas disease is a neglected parasitic infection that affects around six to seven million people, mainly in Latin America. About 30-35% of infected people present chronic Chagas cardiomyopathy (CCC), which eventually leads to death. This condition is characterized by local parasite persistence and leukocyte infiltration. In a murine model of CCC, we observed that among infiltrating leukocytes, CD4+ and CD8+ T cells were in higher frequency in the heart of chronically infected mice, although elevated expression of the regulatory molecules programmed cell death protein 1 (PD1) and PDL1 suggested these cells could be inhibited. To investigate if PD1-PDL1 interaction in the heart of chronically infected mice negatively impacts on the local immune response, facilitating parasite persistence, and progression to CCC, we attempted to recover the local immune response by treating chronically infected mice with anti-PD1 and anti-PDL1-blocking antibodies together with irradiated Trypanosoma cruzi, which provides immune response boosting. Irradiated parasites promote expression of costimulatory molecules in dendritic cells and provide specific parasite antigen, which should aid T cell reactivation upon checkpoint blockade. Following treatment, there was an increased frequency of heart-infiltrating CD4+ and CD8+ T cells with an effector memory phenotype, an increased histopathology score and decreased heart rate, supporting our previous hypothesis of local immunosuppression induced by this pathway during CCC. In addition, blood parasitemia was reduced, which was associated with increased T. cruzi-specific immunoglobulin G 1 antibodies. However, no difference was observed in cytokine production or T. cruzi burden in the hearts of treated mice. Taken together, our results suggest PD1-PDL1 interaction protects the heart from excessive immune response.
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