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

• Published in: Frontiers in immunology Vol. 12; p. 632667
• Main Authors: Garcia de Moura, Renan, Covre, Luciana Polaco, Fantecelle, Carlos Henrique, Gajardo, Vitor Alejandro Torres, Cunha, Carla Baroni, Stringari, Lorenzzo Lyrio, Belew, Ashton Trey, Daniel, Camila Batista, Zeidler, Sandra Ventorin Von, Tadokoro, Carlos Eduardo, de Matos Guedes, Herbert Leonel, Zanotti, Raphael Lubiana, Mosser, David, Falqueto, Aloisio, Akbar, Arne N, Gomes, Daniel Claudio Oliveira
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 09.03.2021
• Subjects: Adult; Cell Proliferation - drug effects; cutaneous leishmaniasis; Female; Humans; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Proteins - metabolism; Immunology; Immunosenescence; Inflammation; inhibitory checkpoint receptors; Interferon-gamma - immunology; Leishmania braziliensis; Leishmania braziliensis - pathogenicity; Leishmaniasis, Cutaneous - immunology; Male; Middle Aged; PD-1; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - metabolism; senescent T cells; Skin - immunology; T cell exhaustion; T-Lymphocyte Subsets - drug effects; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Leishmania braziliensis; immunosenescence; inhibitory checkpoint receptors; T cell exhaustion; senescent T cells; PD-1; cutaneous leishmaniasis
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2021.632667

Patients infected by 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 recall antigen challenge . 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.