title: Combining regulatory T cell depletion and inhibitory receptor blockade improves reactivation of exhausted virus-specific CD8+ T cells and efficiently reduces chronic retroviral loads.
abstract: 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.
authors: Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors: Kirsten K
authors: KK
authors: Dietze
authors: Gennadiy
authors: G
authors: Zelinskyy
authors: Jia
authors: J
authors: Liu
authors: Freya
authors: F
authors: Kretzmer
authors: Simone
authors: S
authors: Schimmer
authors: Ulf
authors: U
authors: Dittmer
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002908:Chronic Disease; D061025:Costimulatory and Inhibitory T-Cell Receptors / Q000037:antagonists & inhibitors* / Q000276:immunology; D005260:Female; D000072597:Hepatitis A Virus Cellular Receptor 2; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology; D011991:Receptors, Virus / Q000037:antagonists & inhibitors / Q000276:immunology; D012190:Retroviridae / Q000276:immunology; D012192:Retroviridae Infections / Q000628:therapy*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D019562:Viral Load; D014780:Viruses / Q000187:drug effects / Q000276:immunology
chemical_list: D000906:Antibodies; D061025:Costimulatory and Inhibitory T-Cell Receptors; C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011991:Receptors, Virus