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.

Altered co-stimulatory and inhibitory receptors on monocyte subsets in patients with visceral leishmaniasis

“…We have recently shown that PD-L1 was increased on all three subsets of monocytes at ToD [23]. Here we extended these results to EoT and show that PD-L1 was significantly decreased on classical and intermediate monocytes.…”

“…Singh et al showed that monocytes isolated from VL patients exhibit an anti-inflammatory phenotype, characterised by decreased parasite phagocytosis and impaired oxidative burst [22]. We have recently shown that PD-L1 is increased on all three subsets of monocytes at the time of VL diagnosis [23]. In the current study, we extend these results to the analyses of other molecules also involved in the modulation of T cell responses, such as CD40, CD80 and CD86.…”

“…All these molecules exist as a soluble form and could interact with their receptors on monocytes: for example, sCTLA-4 could interact with CD80/86 and thereby prevent the binding with CD28 and T cell activation, as shown in autoimmune diseases [39]. The interaction of the inhibitory molecules PD-1 and PD-L1 is better characterised in VL: we have recently shown that IFNg production is improved by inhibition of PD-1/PD-L1 ligation [23]. Therefore, the high expression of both molecules at ToD and their lower expression at EoT is in agreement with the efficiency of the immune response at these two time points [35].…”

“…10 non-endemic male controls with no prior history of VL were recruited amongst the staff of the University of Gondar. The median ages of the three cohorts were similar: VL patients at ToD: 25 [20][21][22][23][24][25][26][27][28][29][30]; VL patients at EoT: 23.5 [18.5-26.8] and controls: 24 [20.5-27.3] years old (p=0.7495). Informed written consent was obtained from each patient and control.…”

CXCR5 and TIM-3 expressions define distinct exhausted T cell subsets in experimental cutaneous infection with Leishmania mexicana

“…CD8 + T cells also provide a protective response through IFN-g production, which amplifies the early differentiation of CD4 + Th1 cells via IL-12 signaling and induces macrophage activation (6). One important mechanism underlying impaired T-cell immunity during either active or chronic human leishmaniasis is the substantial loss of effector functions in a process termed exhaustion (7)(8)(9)(10)(11)(12).…”