Programmed death ligand 2 regulates arginase induction and modifies Trypanosoma cruzi survival in macrophages during murine experimental infection

• Published in: Immunology Vol. 133; no. 1; pp. 29 - 40
• Main Authors: Dulgerian, Laura R., Garrido, Vanina V., Stempin, Cinthia C., Cerbán, Fabio M.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.05.2011; Wiley Subscription Services, Inc; Blackwell Science Inc
• Subjects: Animals; arginase; Arginase - biosynthesis; Arginase - immunology; B7-1 Antigen - immunology; B7-1 Antigen - metabolism; Blotting, Western; Cell Separation; Chagas Disease - immunology; Chagas Disease - metabolism; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; inducible nitric oxide synthase; macrophage; Macrophages - immunology; Macrophages - metabolism; Macrophages - parasitology; Mice; Mice, Inbred BALB C; Mice, Knockout; Nitric Oxide Synthase Type II - immunology; Nitric Oxide Synthase Type II - metabolism; Original; Programmed Cell Death 1 Ligand 2 Protein; programmed death ligand 2; Trypanosoma cruzi; Trypanosoma cruzi - immunology
• ISSN: 0019-2805; 1365-2567
• DOI: 10.1111/j.1365-2567.2011.03406.x

Summary 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.