PD-1/PD-L1 Pathway Modulates Macrophage Susceptibility to Mycobacterium tuberculosis Specific CD8+ T cell Induced Death

• Published in: Scientific reports Vol. 9; no. 1; p. 187
• Main Authors: Suarez, Guadalupe Verónica, Melucci Ganzarain, Claudia del Carmen, Vecchione, María Belén, Trifone, César Ariel, Marín Franco, José Luis, Genoula, Melanie, Moraña, Eduardo José, Balboa, Luciana, Quiroga, Maria Florencia
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.01.2019; Nature Publishing Group
• Subjects: 13/1; 13/106; 13/21; 13/31; 631/250/1619/554/1834/1269; 631/250/2504/342; 692/699/255/1856; 82/80; B7-H1 Antigen - metabolism; Blood Specimen Collection; CD14 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - microbiology; Cell activation; Cell Death; Cytotoxicity; Degranulation; Humanities and Social Sciences; Humans; Immune checkpoint; Infections; Interleukin 10; Interleukin 4; Lymphocytes; Lymphocytes T; Macrophages; Macrophages - microbiology; Macrophages - pathology; Mortality; multidisciplinary; Mycobacterium tuberculosis; Mycobacterium tuberculosis - immunology; PD-1 protein; PD-L1 protein; Peripheral blood mononuclear cells; Pleural effusion; Pleural Effusion - microbiology; Pleurisy; Programmed Cell Death 1 Receptor - metabolism; Science; Science (multidisciplinary); T-Lymphocytes, Cytotoxic - immunology; Tuberculosis; Tuberculosis - immunology; Tuberculosis - prevention & control; γ-Interferon
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-36403-2

CD8 + T cells contribute to tuberculosis (TB) infection control by inducing death of infected macrophages. Mycobacterium tuberculosis ( Mtb ) infection is associated with increased PD-1/PD-L1 expression and alternative activation of macrophages. We aimed to study the role of PD-1 pathway and macrophage polarization on Mtb -specific CD8 + T cell-induced macrophage death. We observed that both PD-L1 on CD14 + cells and PD-1 on CD8 + T cells were highly expressed at the site of infection in pleurisy TB patients’ effusion samples (PEMC). Moreover, a significant increase in CD8 + T cells’ Mtb -specific degranulation from TB-PEMC vs. TB-PBMC was observed, which correlated with PD-1 and PDL-1 expression. In an in vitro model, M1 macrophages were more susceptible to Mtb -specific CD8 + T cells’ cytotoxicity compared to M2a macrophages and involved the transfer of cytolytic effector molecules from CD8 + T lymphocytes to target cells. Additionally, PD-L1 blocking significantly increased the in vitro Ag-specific CD8 + T cell cytotoxicity against IFN-γ-activated macrophages but had no effect over cytotoxicity on IL-4 or IL-10-activated macrophages. Interestingly, PD-L1 blocking enhanced Mtb -specific CD8 + T cell killing of CD14 + cells from human tuberculous pleural effusion samples. Our data indicate that PD-1/PD-L1 pathway modulates antigen-specific cytotoxicity against M1 targets in-vitro and encourage the exploration of checkpoint blockade as new adjuvant for TB therapies.