PD-1 and PD-L1 regulate cellular immunity in canine visceral leishmaniasis

Silva, Kathlenn Liezbeth Oliveira; Chiku, Vanessa Marin; Venturin, Gabriela Luvizotto; Leal, Aline Aparecida Correa; Almeida, Breno Fernando Martins de; Eugênio, Flávia de Rezende; Santos, Paulo Sérgio Patto dos; Machado, Gisele Fabrino; Lima, Valéria Marçal Felix de

doi:10.1016/j.cimid.2018.12.002

Cited by 13 publications

(14 citation statements)

References 38 publications

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“…In both canine and murine models of chronic infection with leishmaniasis, CD4 + and CD8 + T cells express high levels of PD-1 and reduced levels of pro-inflammatory cytokines (120,121). PD-1 blockade in animals infected with Leishmania infantum resulted in enhanced production of IFN-γ and nitric oxide (NO), whereas IL-4 and IL-10 were decreased (69). Blocking PD-L1 in infections with Leishmania donovani leads to T cell proliferation and decreased parasite burden (70).…”

Section: Pd-1 Pathway In Bacterial and Parasitic Infectionsmentioning

confidence: 99%

The Role of PD-1 in Acute and Chronic Infection

et al. 2020

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PD-1 as an immune checkpoint molecule down-regulates T cell activity during immune responses in order to prevent autoimmune tissue damage. In chronic infections or tumors, lasting antigen-exposure leads to permanent PD-1 expression that can limit immune-mediated clearance of pathogens or degenerated cells. Blocking PD-1 can enhance T cell function; in cancer treatment PD-1 blockade is already used as a successful therapy. However, the role of PD-1 expression and blocking in the context of acute and chronic infections is less defined. Building on its success in cancer therapy leads to the hypothesis that blocking PD-1 in infectious diseases is also beneficial in acute or chronic infections. This review will focus on the role of PD-1 expression in acute and chronic infections with virus, bacteria, and parasites, with a particular focus on recent studies regarding PD-1 blockade in infectious diseases.

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Section: Pd-1 Pathway In Bacterial and Parasitic Infectionsmentioning

confidence: 99%

The Role of PD-1 in Acute and Chronic Infection

et al. 2020

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“…To detect PD-1 expression, PBMCs were suspended in PBS containing 1% bovine serum albumin, 0.1% sodium azide and 20% fetal bovine serum, to block the Fc receptor (FcR). Cells were then mixed with either the PE-conjugated monoclonal anti-Human CD279 (PD-1) antibody [18,19] or an isotype control (BD Pharmigen, USA), according to the manufacturer instructions. Ten thousand events were acquired on the FL2 channel of a flow cytometer, and data analysis was performed as described above in the lymphoproliferation assay section (S2 Fig).…”

Section: Flow Cytometry Analysis For Labeling Pd-1 T-bet and Gata3 Imentioning

confidence: 99%

“…The inability of lymphocytes from dogs with leishmaniasis to proliferate and produce Th1 cytokines may be associated, at least in part, with increased PD-1 expression, which promotes apoptosis during the course of infection [18,19]. To assess whether interference in cytokine signaling could lead to reduced PD-1 expression in lymphocytes, PBMCs were cultured with or without SLA using combinations of recombinant canine proteins, or rcasIL-10R1 alone.…”

Section: Combinations Of Rcail12/rcail-2 and Rcail-12/rcail-15 Promotmentioning

confidence: 99%

“…In addition, susceptible dogs present increased expression of programmed cell death 1 (PD-1) and PD-1 ligands (PD-L1 and PDL-2), in splenic cells [18]. Such heightened expression of PD-1 and PD-1 ligands may suppress lymphoproliferation and alters the production of Th1 cytokines, contributing to the development of the disease [19]. Manipulations of certain cytokine signaling pathways may favor control over the parasite in infected individuals [12,13,17,[20][21][22][23].…”

Section: Introductionmentioning

confidence: 99%

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Combined in vitro IL-12 and IL-15 stimulation promotes cellular immune response in dogs with visceral leishmaniasis

et al. 2020

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Domestic dogs are the main reservoir of Leishmania infantum, a causative agent of visceral leishmaniasis (VL). The number of human disease cases is associated with the rate of canine infection. Currently available drugs are not efficient at treating canine leishmaniasis (CanL) and months after the treatment most dogs show disease relapse, therefore the development of new drugs or new therapeutic strategies should be sought. In CanL, dogs lack the ability to mount a specific cellular immune response suitable for combating the parasite and manipulation of cytokine signaling pathway has the potential to form part of effective immunotherapeutic methods. In this study, recombinant canine cytokines (rcaIL-12, rcaIL-2, rcaIL-15 and rcaIL-7) and soluble receptor IL-10R1 (rcasIL-10R1), with antagonistic activity, were evaluated for the first time in combination (rcaIL-12/rcaIL-2, rcaIL-12/rcaIL-15, rcaIL-12/rcasIL-10R1, rcaIL-15/rcaIL-7) or alone (rcasIL-10R1) to evaluate their immunomodulatory capacity in peripheral blood mononuclear cells (PBMCs) from dogs with leishmaniasis. All the combinations of recombinant proteins tested were shown to improve lymphoproliferative response. Further, the combinations rcaIL-12/rcaIL-2 and rcaIL-12/rcaIL-15 promoted a decrease in programmed cell death protein 1 (PD-1) expression in lymphocytes. These same combinations of cytokines and rcaIL-12/rcasIL-10R1 induced IFN-γ and TNF-α production in PBMCs. Furthermore, the combination IL-12/IL-15 led to an increased in T-bet expression in lymphocytes. These findings are encouraging and indicate the use of rcaIL-12 and rcaIL-15 in future in vivo studies aimed at achieving polarization of cellular immune responses in dogs with leishmaniasis, which may contribute to the development of an effective treatment against CanL.

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“…Evidence has highlighted a potentially deleterious role of IRCs during leishmania parasite infection (12)(13)(14)(15)(16)(17). In this scenario, both CTLA-4 and PD-1 are highly expressed by CD8 + T cells from patients with visceral (13,18) and diffuse cutaneous leishmaniasis (19).…”

Section: Introductionmentioning

confidence: 99%

PD-1 Blockade Modulates Functional Activities of Exhausted-Like T Cell in Patients With Cutaneous Leishmaniasis

et al. 2021

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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.

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PD-1 and PD-L1 regulate cellular immunity in canine visceral leishmaniasis

Cited by 13 publications

References 38 publications

The Role of PD-1 in Acute and Chronic Infection

The Role of PD-1 in Acute and Chronic Infection

Combined in vitro IL-12 and IL-15 stimulation promotes cellular immune response in dogs with visceral leishmaniasis

PD-1 Blockade Modulates Functional Activities of Exhausted-Like T Cell in Patients With Cutaneous Leishmaniasis

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