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

Universidade Federal do Espírito Santo. Núcleo de Doenças Infecciosas. Vitória, ES, Brasil.
Universidade Federal do Espírito Santo. Núcleo de Doenças Infecciosas. Vitória, ES, Brasil / Division of Medicine, University College London. London, United Kingdom.
Universidade Federal do Espírito Santo. Núcleo de Doenças Infecciosas. Vitória, ES, Brasil.
Universidade Federal do Espírito Santo. Núcleo de Doenças Infecciosas. Vitória, ES, Brasil.
Universidade Federal do Espírito Santo. Núcleo de Doenças Infecciosas. Vitória, ES, Brasil.
Universidade Federal do Espírito Santo. Núcleo de Doenças Infecciosas. Vitória, ES, Brasil.
Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD, USA / Center for Bioinformatics and Computational Biology, University of Maryland, College Park, MD, United States.
Universidade Federal do Espírito Santo. Núcleo de Biotecnologia. Vitória, ES, Brasil.
Universidade Federal do Espírito Santo. Núcleo de Biotecnologia. Vitória, ES, Brasil.
Universidade Vila Velha. Vila Velha, ES, Brasil.
Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Rio de Janeiro, RJ. Brasil.
Secretaria Estadual de Saúde do Espírito Santo-SESA. Vitoria, ES, Brasil.
Department of Cell Biology and Molecular Genetics, University of Maryland, College Park. MD, United States.
Universidade Federal do Espírito Santo. Departamento de Medicina Social. Vitoria, ES, Brasil.
Division of Medicine, University College London. London, United Kingdom.
Universidade Federal do Espírito Santo. Núcleo de Doenças Infecciosas. Vitória, ES, Brasil / Universidade Federal do Espírito Santo. Núcleo de Biotecnologia. Vitória, ES, Brasil.

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-g production, but not TNF-a 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.

Keywords in Portuguese

Leishmaniose cutânea
Leishmania braziliensis
Exaustão de células T
Células T senescentes
Receptores de checkpoint inibitório
Células T senescentes
Imunosenescência

Keywords

Cutaneous leishmaniasis
Leishmania braziliensis
T cell exhaustion
PD-1
Inhibitory checkpoint receptors
Senescent T cells
Immunosenescence

Publisher

Frontiers Media

Citation

MOURA, Renan Garcia de et al. PD-1 Blockade Modulates Functional Activities of Exhausted-Like T Cell in Patients With Cutaneous Leishmaniasis. Frontiers in Immunology, v. 12, Article 632667, p. 1 - 12, Mar. 2021.

DOI

10.3389/fimmu.2021.632667

ISSN

1664-3224

Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/50263

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