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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Bibliographic Details
Published in:	The Journal of experimental medicine Vol. 218; no. 1
Main Authors:	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
Format:	Journal Article
Language:	English
Published:	United States 04.01.2021
Subjects:	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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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1540-9538 1540-9538
DOI:	10.1084/jem.20182232