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 |
| DOI/URL: | |
| Notes: | Export Date: 1 October 2014 -- Source: Scopus |
