The role of inhibitory receptors and their ligands in immune escape from CD8+ T cells and the establishment of chronic virus infection
Final Report Abstract
Chronic infections with human viruses, such as HIV and HCV, or with mouse viruses such as LCMV or Friend Virus (FV), result in the functional exhaustion of CD8+ T cells. Two main mechanisms have been described that mediate this exhaustion: the expression of inhibitory receptors on CD8+ T cells and the expansion of regulatory T cells (Tregs) that suppress CD8+ T cell activity. Several studies showed that the blockage of one of these pathways results in the 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 the 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.
Publications
- PLoS Pathog. 2013;9(12):e1003798. Combining regulatory T cell depletion and inhibitory receptor blockade improves reactivation of exhausted virus-specific CD8+ T cells and efficiently reduces chronic retroviral loads.
Dietze KK1, Zelinskyy G, Liu J, Kretzmer F, Schimmer S, Dittmer U
(See online at https://doi.org/10.1371/journal.ppat.1003798)
