Vaccination with Leishmania mexicana LPG induces PD-1 in CD8+ and PD-L2 in macrophages thereby suppressing the immune response: A model to assess vaccine efficacy

TL;DR

This study investigates how Leishmania mexicana LPG vaccination influences immune inhibitory molecules, revealing dose-dependent expression of PD-1 and PD-L2 that may suppress immune responses and affect vaccine efficacy.

Contribution

It demonstrates that LPG vaccination and infection levels modulate inhibitory receptor expression, providing insights into vaccine design and immune regulation in leishmaniasis.

Findings

LPG vaccination increases PD-1 expression in CD8+ T cells.

Higher parasite loads elevate PD-1 and reduce PD-L2 expression.

In vitro LPG re-stimulation enhances PD-L2 expression in macrophages.

Abstract

Leishmania lipophosphoglycan is a molecule that has been used as a vaccine candidate, with contradictory results. Since unsuccessful protection could be related to suppressed T cell responses, we analyzed the expression of inhibitory receptor PD-1 in CD8+ and CD4+ lymphocytes and it is ligand PD-L2 in macrophages of BALB/c mice immunized with various doses of Leishmania mexicana LPG and re-stimulated in vitro with different concentrations of LPG. Vaccination with LPG enhanced the expression of PD-1 in CD8+ cells. Activation molecules CD137 were reduced in CD8+ cells from vaccinated mice. In vitro re-stimulation enhanced PD-L2 expression in macrophages of healthy mice in a dose-dependent fashion. The expression of PD-1, PD-L2, and CD137 is modulated according to the amount of LPG used during immunization and in vitro re-stimulation. We analyzed the expression of these molecules in mice infected with 1 x 10'4 or 1 x 10'5 L. mexicana promastigotes and re-stimulated in vitro with LPG. Infection with 1 x 10'5 parasites increased the PD-1 expression in CD8+ and diminished PD-L2 in macrophages. When these CD8+ cells were re-stimulated in vitro with LPG, simulating a second exposure to parasite antigens, PD-1 expression increased significantly more, in a dose-dependent fashion. We conclude that CD8+ T lymphocytes and macrophages express inhibition molecules according to the concentrations of Leishmania LPG and to the parasite load. Vaccination with increased amounts of LPG or infections with higher parasite numbers induces enhanced expression of PD-1 and functional inactivation of CD8+ cells, which can have critical consequences in leishmaniasis since these cells are crucial for disease control.