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J Exp Med. 2014 Aug 25;211(9):1905-18. doi: 10.1084/jem.20132577. Epub 2014 Aug 11.

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

Author information

1
Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322.
2
Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322 Xiangya School of Medicine, Central South University, Changsha, Hunan Province, 410013, China.
3
Department of Microbiology and Immunology, and Department of Medical Oncology and Dana Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA 02115.
4
Howard Hughes Medical Institute, Immunology Program, Sloan-Kettering Institute for Cancer Research, and Ludwig Center at Memorial Sloan-Kettering Cancer Center, New York, NY 10065 Howard Hughes Medical Institute, Immunology Program, Sloan-Kettering Institute for Cancer Research, and Ludwig Center at Memorial Sloan-Kettering Cancer Center, New York, NY 10065 Howard Hughes Medical Institute, Immunology Program, Sloan-Kettering Institute for Cancer Research, and Ludwig Center at Memorial Sloan-Kettering Cancer Center, New York, NY 10065 rahmed@emory.edu rudenska@mskcc.org.
5
Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322 rahmed@emory.edu rudenska@mskcc.org.

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.

PMID:
25113973
PMCID:
PMC4144726
DOI:
10.1084/jem.20132577
[Indexed for MEDLINE]
Free PMC Article

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