PD-1 checkpoint inhibition in Leishmania infection of primary human cells
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Abstract
In this study we investigated the impact of Programmed Death-1/Programmed Death-1 ligand (PD-1/PD-L) axis in an in vitro Leishmania major (Lm) infection model consisting of primary human myeloid and lymphoid cells. Two different PD-1 checkpoint inhibitors (IgG1 and IgG4) were used to modulate the PD-1/PD-L interactions in different Lm-specific T-cell assay setups. As read-outs, Lm-induced T-cell proliferation and Lm infection rate in host cells was assessed.
First, PD-1 ligand expression was demonstrated on three different Lm host cells, namely pro-inflammatory and anti-inflammatory human monocyte-derived macrophages (hMDM1 and hMDM2) and dendritic cells (hMDDC). PD-1 checkpoint blockade had no significant impact on Lm-induced T-cell proliferation or Lm infection rate in a co-culture of Lm-infected host cells together with autologous peripheral blood lymphocytes (PBLs). Using an approach with pre-cultured leucocytes (RESTORE-Assay by Römer et al. 2011) which mimics tissue-like conditions and renders T-cells more responsive to their cognate antigen, revealed a similar picture. Although PD-1 and its ligands were detectable in this assay, no significant differences in T-cell proliferation due to PD-1 checkpoint blockade were observed.
Because PD-1/PD-L interactions are highly prominent during chronic inflammation and antigen stimulation, we investigated an approach using phytohemagglutinin-pre-stimulated PBLs in a co-culture with infected hMDM1, hMDM2 or hMDDC. In this approach, two different PD-1 checkpoint inhibitors (IgG1 and IgG4) increased T-cell effector functions in a similar manner. As a consequence Lm infection decreased, being the most pronounced in hMDDC, compared to hMDM1 and hMDM2. Focusing on hMDDC, effects mediated by PD-1 blockade were shown to be partially TNFα dependent. Moreover, treatment with the therapeutic PD-1 checkpoint inhibitor nivolumab specifically enhanced proliferation of CD4+ T-cells, increased expression of the TH1-specific transcription factor Tbet, T-cell activation markers and cytolytic effector proteins, which at large might be implicated in enhanced parasite killing. 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/PD-L-induced T-cell impairment during infectious disease and its influence on immune effector mechanisms to combat Lm infection.