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

Catherine L Tan ¹, Juhi R Kuchroo ¹, Peter T Sage ¹, Dan Liang ¹, Loise M Francisco ¹, Jessica Buck ¹, Youg Raj Thaker ¹, Qianxia Zhang ², Shannon L McArdel ¹, Vikram R Juneja ¹, Sun Jung Lee ¹, Scott B Lovitch ¹, Christine Lian ³, George F Murphy ³, Bruce R Blazar ⁴, Dario A A Vignali ², Gordon J Freeman ⁵, Arlene H Sharpe ¹

Affiliations

¹ Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA.
² Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA.
³ Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
⁴ Department of Pediatrics, University of Minnesota Medical School, Twin Cities, MN.
⁵ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.

PMID: 33045061
70 References
33 citations

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.

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