Tan and Kuchroo et al. investigated how PD-1 impacts Treg cell activation and function by generating mice lacking PD-1 expression specifically in Tregs. In vitro, PD-1-deficient Tregs exhibited an activated state with increased immunosuppressive activity compared with wild-type Tregs, and in vivo, they ameliorated disease in the EAE autoimmune model and prevented diabetes in NOD mice. The enhanced suppressive activity of Tregs lacking PD-1 was found to result from downregulation of PI3-AKT signaling. Enhanced Treg suppression may counter enhanced T effector cell activity against tumors when PD-1 signaling is blocked by anti-PD-1 therapy.
Contributed by Katherine Turner
ABSTRACT: Inhibitory signals through the PD-1 pathway regulate T cell activation, T cell tolerance, and T cell exhaustion. Studies of PD-1 function have focused primarily on effector T cells. Far less is known about PD-1 function in regulatory T (T reg) cells. To study the role of PD-1 in T reg cells, we generated mice that selectively lack PD-1 in T reg cells. PD-1-deficient T reg cells exhibit an activated phenotype and enhanced immunosuppressive function. The in vivo significance of the potent suppressive capacity of PD-1-deficient T reg cells is illustrated by ameliorated experimental autoimmune encephalomyelitis (EAE) and protection from diabetes in nonobese diabetic (NOD) mice lacking PD-1 selectively in T reg cells. We identified reduced signaling through the PI3K-AKT pathway as a mechanism underlying the enhanced suppressive capacity of PD-1-deficient T reg cells. Our findings demonstrate that cell-intrinsic PD-1 restraint of T reg cells is a significant mechanism by which PD-1 inhibitory signals regulate T cell tolerance and autoimmunity.
Author Info: (1) Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA. (2) Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Wome
Author Info: (1) Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA. (2) Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA. (3) School of Life Sciences, University of Essex, Wivenhoe Park, Colchester, UK. (4) Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA. (5) Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA. (6) Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA. (7) Department of Pediatrics, University of Minnesota Medical School, Twin Cities, MN. (8) Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh PA. (9) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA. (10) Harvard Medical School, Boston, MA.
