Combining regulatory T cell depletion and inhibitory receptor blockade improves reactivation of exhausted virus-specific CD8+ T cells and efficiently reduces chronic retroviral loads

PLoS Pathog. 2013;9(12):e1003798. doi: 10.1371/journal.ppat.1003798. Epub 2013 Dec 5.


Chronic infections with human viruses, such as HIV and HCV, or mouse viruses, such as LCMV or Friend Virus (FV), result in functional exhaustion of CD8(+) T cells. Two main mechanisms have been described that mediate this exhaustion: expression of inhibitory receptors on CD8(+) T cells and expansion of regulatory T cells (Tregs) that suppress CD8(+) T cell activity. Several studies show that blockage of one of these pathways results in reactivation of CD8(+) T cells and partial reduction in chronic viral loads. Using blocking antibodies against PD-1 ligand and Tim-3 and transgenic mice in which Tregs can be selectively ablated, we compared these two treatment strategies and combined them for the first time in a model of chronic retrovirus infection. Blocking inhibitory receptors was more efficient than transient depletion of Tregs in reactivating exhausted CD8(+) T cells and reducing viral set points. However, a combination therapy was superior to any single treatment and further augmented CD8(+) T cell responses and resulted in a sustained reduction in chronic viral loads. These results demonstrate that Tregs and inhibitory receptors are non-overlapping factors in the maintenance of chronic viral infections and that immunotherapies targeting both pathways may be a promising strategy to treat chronic infectious diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / immunology
  • CD8-Positive T-Lymphocytes / immunology*
  • Chronic Disease
  • Costimulatory and Inhibitory T-Cell Receptors / antagonists & inhibitors*
  • Costimulatory and Inhibitory T-Cell Receptors / immunology
  • Female
  • Hepatitis A Virus Cellular Receptor 2
  • Lymphocyte Activation*
  • Lymphocyte Depletion*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Programmed Cell Death 1 Receptor / immunology
  • Receptors, Virus / antagonists & inhibitors
  • Receptors, Virus / immunology
  • Retroviridae / immunology
  • Retroviridae Infections / therapy*
  • T-Lymphocytes, Regulatory / immunology*
  • Viral Load
  • Viruses / drug effects
  • Viruses / immunology


  • Antibodies
  • Costimulatory and Inhibitory T-Cell Receptors
  • Havcr2 protein, mouse
  • Hepatitis A Virus Cellular Receptor 2
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Receptors, Virus

Grants and funding

This work was supported by the German Research Association (DFG) Transregio 60 project B4 and DI 1914/1-1. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.