To understand the drivers of Treg immunosuppression, Gocher-Demske et al. used LCMV and influenza infection models and genetic knockouts to show that IFNγ, derived mostly from CD8+ T cells, stimulated a stable TH1 program in Tregs, which subsequently limited CD8+ T cell inflammation. TH1 Tregs were highly immunosuppressive toward antigen-specific CD8+ T cells, reduced CD8+ memory cell formation, and limited the magnitude of CD8+ T cell vaccine responses. Treg-specific absence of the IFNγ receptor resulted in less suppressive TH2 Tregs, with concomitant weight loss and some signs of tissue pathology. IL-12 had little effect on the TH phenotype in the viral models.
Contributed by Ed Fritsch
ABSTRACT: Regulatory T (Treg) cells are an immunosuppressive population that are required to maintain peripheral tolerance and prevent tissue damage from immunopathology, via anti-inflammatory cytokines, inhibitor receptors and metabolic disruption. Here we show that Treg cells acquire an effector-like state, yet remain stable and functional, when exposed to interferon gamma (IFNγ) during infection with lymphocytic choriomeningitis and influenza A virus. Treg cell-restricted deletion of the IFNγ receptor (encoded by Ifngr1), but not the interleukin 12 (IL12) receptor (encoded by Il12rb2), prevented TH1-like polarization (decreased expression of T-bet, CXC motif chemokine receptor 3 and IFNγ) and promoted TH2-like polarization (increased expression of GATA-3, CCR4 and IL4). TH1-like Treg cells limited CD8+ T cell effector function, proliferation and memory formation during acute and chronic infection. These findings provide fundamental insights into how Treg cells sense inflammatory cues from the environment (such as IFNγ) during viral infection to provide guidance to the effector immune response. This regulatory circuit prevents prolonged immunoinflammatory responses and shapes the quality and quantity of the memory T cell response.
Author Info: (1) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh
Author Info: (1) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA. (2) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA. (3) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (4) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA. (5) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA. (6) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA. (7) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA. (8) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Program in Infectious Diseases and Microbiology, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA. (9) Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA. Program in Microbiology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (10) Program in Infectious Diseases and Microbiology, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA. Program in Microbiology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (11) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (12) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (13) Program in Infectious Diseases and Microbiology, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA. (14) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. (15) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA. (16) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. dvignali@pitt.edu. Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA. dvignali@pitt.edu. Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA. dvignali@pitt.edu.
