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

Authors: Penaloza-MacMaster, P.; Kamphorst, A. O.; Wieland, A.; Araki, K.; Iyer, S. S.; West, E. E.; O'Mara, L.; Yang, S.; Konieczny, B. T.; Sharpe, A. H.; Freeman, G. J.; Rudensky, A. Y.; Ahmed, R.
Article Title: Interplay between regulatory T cells and PD-1 in modulating T cell exhaustion and viral control during chronic LCMV infection
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. © 2014 Penaloza-MacMaster et al.
Keywords: signal transduction; adult; controlled study; protein expression; nonhuman; cd8+ t lymphocyte; animal cell; mouse; infection; animal experiment; animal model; regulatory t lymphocyte; cellular immunity; cd4+ t lymphocyte; immunomodulation; upregulation; molecular interaction; virus load; t cell depletion; t lymphocyte activation; b7 antigen; persistent infection; virus immunity; lymphocytotoxicity; programmed death 1 receptor; lymphocytic choriomeningitis virus; exhaustion; viral clearance; priority journal; article; arenavirus infection; t cell exhaustion
Journal Title: Journal of Experimental Medicine
Volume: 211
Issue: 9
ISSN: 0022-1007
Publisher: Rockefeller University Press  
Date Published: 2014-08-25
Start Page: 1905
End Page: 1918
Language: English
DOI: 10.1084/jem.20132577
PROVIDER: scopus
PMCID: PMC4144726
PUBMED: 25113973
Notes: Export Date: 1 October 2014 -- Source: Scopus
Citation Impact
MSK Authors
  1. Alexander Rudensky
    132 Rudensky