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

Pablo Penaloza-MacMaster, Alice O. Kamphorst, Andreas Wieland, Koichi Araki, Smita Iyer, Erin E. West, Leigh O'Mara, Shu Yang, Bogumila T. Konieczny, Arlene H. Sharpe, Gordon J. Freeman, Alexander Y. Rudensky, Rafi Ahmed

Research output: Contribution to journalArticle

125 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1905-1918
Number of pages14
JournalJournal of Experimental Medicine
Volume211
Issue number9
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

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    Penaloza-MacMaster, P., Kamphorst, A. O., Wieland, A., Araki, K., Iyer, S., West, E. E., O'Mara, L., Yang, S., Konieczny, B. T., Sharpe, A. H., Freeman, G. J., Rudensky, A. Y., & Ahmed, R. (2014). Interplay between regulatory T cells and PD-1 in modulating T cell exhaustion and viral control during chronic LCMV infection. Journal of Experimental Medicine, 211(9), 1905-1918. https://doi.org/10.1084/jem.20132577