PD-1 restraint of regulatory T cell suppressive activity is critical for immune tolerance

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 gene...

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Vydané v:	The Journal of experimental medicine Ročník 218; číslo 1
Hlavní autori:	Tan, Catherine L, Kuchroo, Juhi R, Sage, Peter T, Liang, Dan, Francisco, Loise M, Buck, Jessica, Thaker, Youg Raj, Zhang, Qianxia, McArdel, Shannon L, Juneja, Vikram R, Lee, Sun Jung, Lovitch, Scott B, Lian, Christine, Murphy, George F, Blazar, Bruce R, Vignali, Dario A A, Freeman, Gordon J, Sharpe, Arlene H
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States 04.01.2021
Predmet:	Animals Diabetes Mellitus, Experimental - genetics Diabetes Mellitus, Experimental - immunology Encephalomyelitis, Autoimmune, Experimental - genetics Encephalomyelitis, Autoimmune, Experimental - immunology Immune Tolerance Mice Mice, Inbred NOD Mice, Neurologic Mutants Phosphatidylinositol 3-Kinases - genetics Phosphatidylinositol 3-Kinases - immunology Programmed Cell Death 1 Receptor - genetics Programmed Cell Death 1 Receptor - immunology Proto-Oncogene Proteins c-akt - genetics Proto-Oncogene Proteins c-akt - immunology Signal Transduction - genetics Signal Transduction - immunology T-Lymphocytes, Regulatory - immunology
ISSN:	1540-9538, 1540-9538
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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.
AbstractList	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.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. 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	Lee, Sun Jung Thaker, Youg Raj Zhang, Qianxia Buck, Jessica Murphy, George F Francisco, Loise M Blazar, Bruce R Sharpe, Arlene H Vignali, Dario A A Freeman, Gordon J Kuchroo, Juhi R McArdel, Shannon L Sage, Peter T Lian, Christine Tan, Catherine L Juneja, Vikram R Lovitch, Scott B Liang, Dan
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Snippet	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...
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SubjectTerms	Animals Diabetes Mellitus, Experimental - genetics Diabetes Mellitus, Experimental - immunology Encephalomyelitis, Autoimmune, Experimental - genetics Encephalomyelitis, Autoimmune, Experimental - immunology Immune Tolerance Mice Mice, Inbred NOD Mice, Neurologic Mutants Phosphatidylinositol 3-Kinases - genetics Phosphatidylinositol 3-Kinases - immunology Programmed Cell Death 1 Receptor - genetics Programmed Cell Death 1 Receptor - immunology Proto-Oncogene Proteins c-akt - genetics Proto-Oncogene Proteins c-akt - immunology Signal Transduction - genetics Signal Transduction - immunology T-Lymphocytes, Regulatory - immunology
Title	PD-1 restraint of regulatory T cell suppressive activity is critical for immune tolerance
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