Impaired in vitro Interferon-γ production in patients with visceral leishmaniasis is improved by inhibition of PD1/PDL-1 ligation

Abstract

Visceral leishmaniasis (VL) is a neglected tropical disease that causes substantial morbidity and mortality and is a growing health problem in Ethiopia, where this study took place. Most individuals infected with Leishmania donovani parasites will stay asymptomatic, but some develop VL that, if left untreated, is almost always fatal. This stage of the disease is associated with a profound immunosuppression, characterised by impaired production of Interferonγ (IFNγ), a cytokine that plays a key role in the control of Leishmania parasites, and high expression levels of an inhibitory receptor, programmed cell death 1 (PD1) on CD4⁺ T cells. Here, we tested the contribution of the interaction between the immune checkpoint PD1 and its ligand PDL-1 on the impaired production of IFNγ in VL patients. Our results show that in the blood of VL patients, not only CD4⁺, but also CD8⁺ T cells express high levels of PD1 at the time of VL diagnosis. Next, we identified PDL-1 expression on different monocyte subsets and neutrophils and show that PDL-1 levels were significantly increased in VL patients. PD1/PDL-1 inhibition resulted in significantly increased production of IFNγ, suggesting that therapy using immune checkpoint inhibitors might improve disease control in these patients. Visceral leishmaniasis is a neglected tropical disease, that affects the poorest of the poor in low and middle-income countries. It is caused by a parasite, Leishmania, that is transmitted during the blood meal of an insect. When individuals cannot control Leishmania replication, they develop visceral leishmaniasis, that is characterised by enlarged spleen and liver, low blood cell counts and wasting. We have previously shown that lymphocytes from these patients have an impaired ability to produce a soluble mediator, IFNγ, that contribute to the killing of the parasites, but that this was restored after successful anti-leishmanial treatment. Here we identified high expression levels of a marker, PD1, on lymphocyte; that has been associated with dysfunctional lymphocytes. We also identified the ligands of this marker, PDL1, on different blood cells. Furthermore, we showed that blocking the interaction between PD1 and PDL1 resulted in increased levels of IFNγ. These results suggest that treatment that blocks the interaction of PD1 with PDL1 might improve disease management and patient care.