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.
Skip Nav Destination
Close
Article navigation
4 January 2021
Article|
October 06 2020
PD-1 restraint of regulatory T cell suppressive activity is critical for immune tolerance
Catherine L. Tan,
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
Search for other works by this author on:
Juhi R. Kuchroo,
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
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
Search for other works by this author on:
Peter T. Sage,
Peter T. Sage
Conceptualization, Methodology, Writing - review & editing
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
Search for other works by this author on:
Dan Liang,
Dan Liang
Investigation, Validation, Writing - review & editing
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
Search for other works by this author on:
Loise M. Francisco,
Loise M. Francisco
Conceptualization, Formal analysis, Investigation, Methodology, Writing - original draft
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
Search for other works by this author on:
Jessica Buck,
Jessica Buck
Conceptualization, Investigation, Methodology, Validation, Writing - review & editing
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
Search for other works by this author on:
Youg Raj Thaker,
Youg Raj Thaker
Conceptualization, Methodology, Resources, Visualization, Writing - review & editing
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
Search for other works by this author on:
Qianxia Zhang,
Qianxia Zhang
Conceptualization, Formal analysis, Investigation, Methodology, Validation
4
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA
5
Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA
Search for other works by this author on:
Shannon L. McArdel,
Shannon L. McArdel
Investigation
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
Search for other works by this author on:
Vikram R. Juneja,
Vikram R. Juneja
Investigation, Methodology
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
Search for other works by this author on:
Sun Jung Lee,
Sun Jung Lee
Investigation, Resources
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
Search for other works by this author on:
Scott B. Lovitch,
Scott B. Lovitch
Methodology, Writing - review & editing
1
Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA
6
Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
Search for other works by this author on:
Christine Lian,
Christine Lian
Data curation, Formal analysis, Writing - review & editing
6
Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
Search for other works by this author on:
George F. Murphy,
George F. Murphy
Data curation, Resources, Validation, Writing - review & editing
6
Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
Search for other works by this author on:
Bruce R. Blazar,
Bruce R. Blazar
Conceptualization, Funding acquisition, Writing - review & editing
7
Department of Pediatrics, University of Minnesota Medical School, Twin Cities, MN
Search for other works by this author on:
Dario A.A. Vignali,
Dario A.A. Vignali
Funding acquisition, Supervision, Validation, Writing - review & editing
4
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA
5
Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA
8
Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh PA
Search for other works by this author on:
Gordon J. Freeman,
Gordon J. Freeman
Conceptualization, Funding acquisition, Methodology, Resources, Writing - review & editing
9
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
10
Harvard Medical School, Boston, MA
Search for other works by this author on:
Arlene H. Sharpe
Conceptualization, Funding acquisition, Methodology, Project administration, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
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
6
Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
Correspondence to Arlene H. Sharpe: arlene_sharpe@hms.harvard.edu
Search for other works by this author on:
Catherine L. Tan
Validation, Visualization, Writing - original draft, Writing - review & editing
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
Juhi R. Kuchroo
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
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
Peter T. Sage
Conceptualization, Methodology, Writing - review & editing
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
Dan Liang
Investigation, Validation, Writing - review & editing
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
Loise M. Francisco
Conceptualization, Formal analysis, Investigation, Methodology, Writing - original draft
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
Jessica Buck
Conceptualization, Investigation, Methodology, Validation, Writing - review & editing
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
Youg Raj Thaker
Conceptualization, Methodology, Resources, Visualization, Writing - review & editing
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
Qianxia Zhang
Conceptualization, Formal analysis, Investigation, Methodology, Validation
4
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA
5
Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA
Shannon L. McArdel
Investigation
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
Vikram R. Juneja
Investigation, Methodology
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
Sun Jung Lee
Investigation, Resources
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
Scott B. Lovitch
Methodology, Writing - review & editing
1
Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA
6
Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
Christine Lian
Data curation, Formal analysis, Writing - review & editing
6
Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
George F. Murphy
Data curation, Resources, Validation, Writing - review & editing
6
Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
Bruce R. Blazar
Conceptualization, Funding acquisition, Writing - review & editing
7
Department of Pediatrics, University of Minnesota Medical School, Twin Cities, MN
Dario A.A. Vignali
Funding acquisition, Supervision, Validation, Writing - review & editing
4
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA
5
Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA
8
Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh PA
Gordon J. Freeman
Conceptualization, Funding acquisition, Methodology, Resources, Writing - review & editing
9
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
10
Harvard Medical School, Boston, MA
Arlene H. Sharpe
Conceptualization, Funding acquisition, Methodology, Project administration, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
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
6
Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
Correspondence to Arlene H. Sharpe: arlene_sharpe@hms.harvard.edu
*
C.L. Tan and J.R. Kuchroo contributed equally to this paper.
Received:
December 03 2018
Revision Received:
June 30 2020
Accepted:
August 26 2020
Online Issn: 1540-9538
Print Issn: 0022-1007
Funding:
National Institute of General Medical Sciences
(T32GM007753)
National Institutes of Health
(NO AWARD)
National Multiple Sclerosis Society
(NO AWARD)
National Science Foundation
(NO AWARD)
© 2020 Tan et al.
2020
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Exp Med (2021) 218 (1): e20182232.
Article history
Received:
December 03 2018
Revision Received:
June 30 2020
Accepted:
August 26 2020
Citation
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
Download citation file:
Close
Sign in
Don't already have an account? Register
Client Account
You could not be signed in. Please check your email address / username and password and try again.
Sign in via your Institution
Sign in via your Institution
5,016
Views
0
Citations
Advertisement