Nivolumab Enhances In Vitro Effector Functions of PD-1+ T-Lymphocytes and Leishmania-Infected Human Myeloid Cells in a Host Cell-Dependent Manner.

Christodoulos Filippis,Peter Crauwels,Zoe Waibler,Gaetan Aime Noubissi Nzeteu,Ger Van Zandbergen,Katharina Arens,Gabriele Reichmann

doi:10.3389/fimmu.2017.01880

Christodoulos Filippis, Peter Crauwels + Show 5 more

Open Access

https://doi.org/10.3389/fimmu.2017.01880

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Abstract

Functional impairment of T-cells and a concomitant augmented expression of programmed death-1 (PD-1) have been observed in visceral leishmaniasis patients, as well as in experimental models for visceral and cutaneous leishmaniasis. The PD-1/PD-1-ligand (PD-1/PD-L) interaction negatively regulates T-cell effector functions, which are required for parasite control during leishmaniasis. The aim of this study was to elucidate the impact of the PD-1/PD-L axis in a human primary in vitro infection model of Leishmania major (Lm). Blocking the PD-1/PD-L interaction with nivolumab increased T-cell proliferation and release of the proinflammatory cytokines TNFα and IFNγ during the cocultivation of Lm-infected human monocyte-derived macrophages (hMDMs) or dendritic cells (hMDDC) with autologous PD-1+-lymphocytes. As a consequence Lm infection decreased, being the most pronounced in hMDDC, compared to proinflammatory hMDM1 and anti-inflammatory hMDM2. Focusing on hMDDC, we could partially reverse effects mediated by PD-1 blockade by neutralizing TNFα but not by neutralizing IFNγ. Furthermore, PD-1 blockade increased intracellular expression of perforin, granulysin, and granzymes in proliferating CD4+-T-cells, which might be implicated in reduction of Lm-infected cells. In all, our data describe an important role for the PD-1/PD-L axis upon Lm infection using a human primary cell system. These data contribute to a better understanding of the PD-1-induced T-cell impairment during disease and its influence on immune effector mechanisms to combat Lm infection.

Highlights

The parasitic disease leishmaniasis is still endemic in 97 countries, causing up to 30,000 deaths annually, a number potentially increasing due to climate changes and global warming [1]
Basal surface expression of PD-L1 on human monocyte-derived dendritic cells (hMDDC) (RFI: 2.13 ± 0.37) was higher compared to human monocyte-derived macrophages type 1 (hMDM1) or human monocyte-derived macrophages type 2 (hMDM2), which did not increase upon Leishmania major (Lm) infection (RFI: 2.33 ± 0.36) (Figure 1A)
We show that PD-L1 and PD-L2 are expressed on all three host cell types and their expression is partially upregulated by Lm infec tion, which is a prerequisite to modulate the programmed death-1 (PD-1)/PD-L axis by anti-PD-1 blockade

Summary

Introduction

The parasitic disease leishmaniasis is still endemic in 97 countries, causing up to 30,000 deaths annually, a number potentially increasing due to climate changes and global warming [1]. Several in vitro studies demonstrated Leishmania-naive healthy human donors to possess a natural T-cell response against live parasites, antigen extracts or specific components of different Leishmania strains [9,10,11,12,13,14,15,16]. This early MHC class II dependent T-cell response was shown to dampen Leishmania parasite burden in autologous human macrophage/T-cell cocultures [11]. The activation of CD8+- and CD4+-T-cells is regulated by various signals such as costimulatory molecules, which can either positively or nega tively influence T-cell priming

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