Abstract
Patients infected by Leishmania braziliensis develop debilitating skin lesions. The role of inhibitory checkpoint receptors (ICRs) that induce T cell exhaustion during this disease is not known. Transcriptional profiling identified increased expression of ICRs including PD-1, PDL-1, PDL-2, TIM-3, and CTLA-4 in skin lesions of patients that was confirmed by immunohistology where there was increased expression of PD-1, TIM-3, and CTLA-4 in both CD4+ and CD8+ T cell subsets. Moreover, PDL-1/PDL-2 ligands were increased on skin macrophages compared to healthy controls. The proportions PD1+, but not TIM-3 or CTLA-4 expressing T cells in the circulation were positively correlated with those in the lesions of the same patients, suggesting that PD-1 may regulate T cell function equally in both compartments. Blocking PD-1 signaling in circulating T cells enhanced their proliferative capacity and IFN-γ production, but not TNF-α secretion in response to L. braziliensis recall antigen challenge in vitro. While we previously showed a significant correlation between the accumulation of senescent CD8+CD45RA+CD27- T cells in the circulation and skin lesion size in the patients, there was no such correlation between the extent of PD-1 expression by circulating on T cells and the magnitude of skin lesions suggesting that exhausted-like T cells may not contribute to the cutaneous immunopathology. Nevertheless, we identified exhausted-like T cells in both skin lesions and in the blood. Targeting this population by PD-1 blockade may improve T cell function and thus accelerate parasite clearance that would reduce the cutaneous pathology in cutaneous leishmaniasis.
Highlights
Leishmaniasis is caused by intracellular parasites belonging to Leishmania genus and has a global estimated prevalence of 12 million infected people, with 2 million new cases reported annually worldwide [1]
We found 9,955 genes identified as differentially expressed between the two groups that included inhibitory checkpoint receptors and their ligands that were uniquely associated with patient skin lesions (Figures 1B, C)
We investigated whether blockade of programmed death 1 (PD-1) signaling of circulating CD4+ and CD8+ T cells from cutaneous leishmaniasis (CL) patients, using antibodies to its ligands PDL-1 and PDL-2 blockade could enhance specific T cell functions linked to a leishmanicidal response after stimulation with L. braziliensis antigen (LbAg)
Summary
Leishmaniasis is caused by intracellular parasites belonging to Leishmania genus and has a global estimated prevalence of 12 million infected people, with 2 million new cases reported annually worldwide [1]. Leishmania braziliensis is the most prevalent of the cutaneous species in Brazil, causing chronic infections and skin tissue damage associated with a wide spectrum of clinical manifestations [2, 3]. Increased production of TNF-a and non-specific cytotoxic mechanisms are linked to skin inflammation and lesion pathology [6, 7]. The absence of inhibitory mechanisms has been correlated with tissue damage and severity of CL [8]. Both insufficient and hyperactive non-specific immune responses may lead to pathology and provide avenues for therapeutic intervention
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