Programmed death-1–induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection

• Published in: Nature medicine Vol. 16; no. 4; pp. 452 - 459
• Main Authors: Said, Elias A, Dupuy, Franck P, Trautmann, Lydie, Zhang, Yuwei, Shi, Yu, El-Far, Mohamed, Hill, Brenna J, Noto, Alessandra, Ancuta, Petronela, Peretz, Yoav, Fonseca, Simone G, Van Grevenynghe, Julien, Boulassel, Mohamed R, Bruneau, Julie, Shoukry, Naglaa H, Routy, Jean-Pierre, Douek, Daniel C, Haddad, Elias K, Sekaly, Rafick-Pierre
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.04.2010; Nature Publishing Group
• Subjects: 631/250/2152/1566/1618; 631/326/596/2555; 631/337; 692/699/249/1570/1901; Animal models; Antigens, CD - biosynthesis; Antigens, CD - physiology; B7-H1 Antigen; Biomedical and Life Sciences; Biomedicine; Blood; Cancer Research; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - physiology; CD4-Positive T-Lymphocytes - virology; Cellular biology; Cytokines; HIV; HIV Infections - immunology; HIV Infections - physiopathology; Human immunodeficiency virus; Humans; Immunology; Infectious Diseases; Interleukin-10 - biosynthesis; Interleukin-10 - physiology; Lymphocyte Activation - immunology; Lymphocyte Activation - physiology; Lymphocyte Subsets - immunology; Lymphocyte Subsets - physiology; Metabolic Diseases; Microbiology; Molecular Medicine; Monocytes - immunology; Monocytes - physiology; Mortality; Neurosciences; Phosphorylation; Receptors, IgG - immunology; Receptors, IgG - physiology; STAT3 Transcription Factor - immunology; STAT3 Transcription Factor - physiology; Translocation; Up-Regulation - physiology; Viremia - immunology; Viremia - physiopathology
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/nm.2106

Programmed death-1 (PD-1) and interleukin-10 (IL-10) impair T cell function during chronic viral infections. Microbial products are now found to inhibit T cell function during HIV infection by upregulating PD-1 and IL-10 production by monocytes. Viral replication and microbial translocation from the gut to the blood during HIV infection lead to hyperimmune activation, which contributes to the decline in CD4 + T cell numbers during HIV infection. Programmed death-1 (PD-1) and interleukin-10 (IL-10) are both upregulated during HIV infection. Blocking interactions between PD-1 and programmed death ligand-1 (PD-L1) and between IL-10 and IL-10 receptor (IL-10R) results in viral clearance and improves T cell function in animal models of chronic viral infections. Here we show that high amounts of microbial products and inflammatory cytokines in the plasma of HIV-infected subjects lead to upregulation of PD-1 expression on monocytes that correlates with high plasma concentrations of IL-10. Triggering of PD-1 expressed on monocytes by PD-L1 expressed on various cell types induced IL-10 production and led to reversible CD4 + T cell dysfunction. We describe a new function for PD-1 whereby microbial products inhibit T cell expansion and function by upregulating PD-1 levels and IL-10 production by monocytes after binding of PD-1 by PD-L1.