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.
PD-1 restraint of regulatory T cell suppressive activity is critical for immune tolerance
Disclosures: P.T. Sage reported a patent to PCT/US16/57031 pending. L.M. Francisco reported "other" from Evelo Biosciences and GlaxoSmithKline outside the submitted work; in addition, L.M. Francisco had a patent to US Patent 10,577,586 pending, a patent to WO2017066561A2 pending, and a patent to US20150299322A1 with royalties paid; and is currently an employee of Evelo Biosciences. V.R. Juneja reported a patent number 20180303922 issued. B.R. Blazar reported grants from the National Institutes of Health and personal fees from BlueRock Therapeutics, Magenta Therapeutics, Kadmon Pharmaceuticals, Incyte Corp, Obsidian Therapeutics, Regeneron Pharmaceuticals, Regimmune, Dr. Reddy, and Equillium Inc. outside the submitted work. D.A.A. Vignali reported personal fees from Almirall outside the submitted work and reported, "cofounder and stock holder - Novasenta and Tizona; stock holder - Oncorus and Werewolf; patents licensed and royalties - Astellas, BMS; scientific advisory board member - Tizona, Werewolf and F-Star; consultant - Astellas, BMS, Almirall; research funding - BMS, Astellas and Novasenta." G.J. Freeman reported a patent with royalties paid (Roche); a patent with royalties paid (Merck MSD); a patent with royalties paid (Bristol-Myers Squibb); a patent with royalties paid (Merck KGA); a patent with royalties paid (Boehringer-Ingelheim); a patent with royalties paid (AstraZeneca); a patent with royalties paid (Dako); a patent with royalties paid (Leica); a patent with royalties paid (Novartis); and a patent with royalties paid (Mayo Clinic). G.J. Freeman has served on advisory boards for Roche, Bristol-Myers-Squibb, Xios, Origimed, Triursus, iTeos, NextPoint, IgM, Jubilant and GV20, and has equity in Nextpoint, Triursus, Xios, iTeos, IgM, and GV20. A.H. Sharpe reported personal fees from Surface Oncology, Sqz Biotech, Selecta, Elstar, and Elpiscience; "other" from Monopteros; grants from Novartis, Merck, Roche, Ipsen, UCB, and Quark Ventures outside the submitted work; and is on the scientific advisory boards for the Massachusetts General Cancer Center, Program in Cellular and Molecular Medicine at Boston Children's Hospital and the Human Oncology and Pathogenesis Program at Memorial Sloan Kettering Cancer Center and Scientific Editor for the Journal of Experimental Medicine. A.H. Sharpe reported the following patents: 7,432,059, with royalties paid (Roche, Merck, Bristol-Myers-Squibb, EMD-Serono, Boehringer-Ingelheim, AstraZeneca, Leica, Mayo Clinic, Dako and Novartis); 7,722,868, with royalties paid (Roche, Merck, Bristol-Myers-Squibb, EMD-Serono, Boehringer-Ingelheim, AstraZeneca, Leica, Mayo Clinic, Dako and Novartis); 8,652,465, licensed (Roche), 9,457,080, licensed (Roche); 9,683,048, licensed (Novartis); 9,815,898, licensed (Novartis); 9,845,356, licensed (Novartis); 10,202,454, licensed (Novartis); 10,457,733, licensed (Novartis); 9,580,684, issued; 9,988,452, issued; 10,370,446, issued. No other disclosures were reported.
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Catherine L. Tan, Juhi R. Kuchroo, Peter T. Sage, Dan Liang, Loise M. Francisco, Jessica Buck, Youg Raj Thaker, Qianxia Zhang, Shannon L. McArdel, Vikram R. Juneja, Sun Jung Lee, Scott B. Lovitch, Christine Lian, George F. Murphy, Bruce R. Blazar, Dario A.A. Vignali, Gordon J. Freeman, Arlene H. Sharpe; PD-1 restraint of regulatory T cell suppressive activity is critical for immune tolerance. J Exp Med 4 January 2021; 218 (1): e20182232. doi: https://doi.org/10.1084/jem.20182232
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