Interplay between regulatory T cells and PD-1 in modulating T cell exhaustion and viral control during chronic LCMV infection

• Type of Material: Article
• Authors: Pablo Penaloza-MacMaster, Emory University; Alice O Kamphorst Silva, Emory University; Andreas Wieland, Emory University; Koichi Araki, Emory University; Smita S. Iyer, Emory University; Erin E. West, Emory University; Leigh O’Mara, Emory University; Shu Yang, Emory University; Bogumila T. Konieczny, Emory University; Arlene H. Sharpe, Harvard Medical School; Gordon J. Freeman, Harvard Medical School; Alexander Y. Rudensky, Howard Hughes Medical Institute; Rafi Ahmed, Emory University
• Language: English
• Date: 2014-08-25
• Publisher: Rockefeller University Press
• Publication Version: Final Published Version
• Copyright Statement: © 2014 Penaloza-MacMaster et al.
• License: Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1084/jem.20132577
• Title of Journal or Parent Work: Journal of Experimental Medicine
• ISSN: 0022-1007
• Volume: 211
• Issue: 9
• Start Page: 1905
• End Page: 1918
• Grant/Funding Information: This work was supported by National Institutes of Health grants R01 AI3004 (R. Ahmed), P01 AI080192 (R. Ahmed and G.J. Freeman), P01 AI056299 (R. Ahmed, G.J. Freeman, and A.H. Sharpe), and R37 AI034206 (A.Y. Rudensky), by the Ludwig Cancer Research (A.Y. Rudensky), and by the Cancer Research Institute’s Irvington Institute Fellowship Program (A.O. Kamphorst).; A.Y. Rudensky is an investigator with the Howard Hughes Medical Institute.
• Keywords: FUNCTIONAL IMPAIRMENT; EXPRESSION; GRANZYME-B; ANTITUMOR IMMUNITY; EFFECTOR; MEDIATED SUPPRESSION; LYMPHOCYTIC CHORIOMENINGITIS VIRUS; IN-VIVO; Life Sciences & Biomedicine; Research & Experimental Medicine; Medicine, Research & Experimental; Immunology; MEMORY CELLS; PERSISTENCE; Science & Technology
• Research Categories: Biology, Virology; Health Sciences, Immunology

Abstract

Regulatory T (T reg) cells are critical for preventing autoimmunity mediated by self-reactive T cells, but their role in modulating immune responses during chronic viral infection is not well defined. To address this question and to investigate a role for T reg cells in exhaustion of virus-specific CD8 T cells, we depleted T reg cells in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). T reg cell ablation resulted in 10-100-fold expansion of functional LCMV-specific CD8 T cells. Rescue of exhausted CD8 T cells was dependent on cognate antigen, B7 costimulation, and conventional CD4 T cells. Despite the striking recovery of LCMV-specific CD8 T cell responses, T reg cell depletion failed to diminish viral load. Interestingly, T reg cell ablation triggered up-regulation of the molecule programmed cell death ligand-1 (PD-L1), which upon binding PD-1 on T cells delivers inhibitory signals. Increased PD-L1 expression was observed especially on LCMV-infected cells, and combining T reg cell depletion with PD-L1 blockade resulted in a significant reduction in viral titers, which was more pronounced than that upon PD-L1 blockade alone. These results suggest that T reg cells effectively maintain CD8 T cell exhaustion, but blockade of the PD-1 inhibitory pathway is critical for elimination of infected cells.