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Nature. 2018 Jun;558(7710):454-459. doi: 10.1038/s41586-018-0206-z. Epub 2018 Jun 13.

Induction and transcriptional regulation of the co-inhibitory gene module in T cells.

Author information

1
Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA.
2
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
3
Celsius Therapeutics, Cambridge, MA, USA.
4
Rheumatology Research Group, Center for Translational Inflammation Research, Queen Elizabeth Hospital, Birmingham, UK.
5
Pulmonary and Critical Care Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
6
Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. acanderson@partners.org.
7
Broad Institute of MIT and Harvard, Cambridge, MA, USA. acanderson@partners.org.
8
Broad Institute of MIT and Harvard, Cambridge, MA, USA. aregev@broadinstitute.org.
9
Howard Hughes Medical Institute, Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. aregev@broadinstitute.org.
10
Department of Biology, Koch Institute and Ludwig Center, Massachusetts Institute of Technology, Cambridge, MA, USA. aregev@broadinstitute.org.
11
Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA. vkuchroo@evergrande.hms.harvard.edu.
12
Broad Institute of MIT and Harvard, Cambridge, MA, USA. vkuchroo@evergrande.hms.harvard.edu.

Abstract

The expression of co-inhibitory receptors, such as CTLA-4 and PD-1, on effector T cells is a key mechanism for ensuring immune homeostasis. Dysregulated expression of co-inhibitory receptors on CD4+ T cells promotes autoimmunity, whereas sustained overexpression on CD8+ T cells promotes T cell dysfunction or exhaustion, leading to impaired ability to clear chronic viral infections and diseases such as cancer1,2. Here, using RNA and protein expression profiling at single-cell resolution in mouse cells, we identify a module of co-inhibitory receptors that includes not only several known co-inhibitory receptors (PD-1, TIM-3, LAG-3 and TIGIT) but also many new surface receptors. We functionally validated two new co-inhibitory receptors, activated protein C receptor (PROCR) and podoplanin (PDPN). The module of co-inhibitory receptors is co-expressed in both CD4+ and CD8+ T cells and is part of a larger co-inhibitory gene program that is shared by non-responsive T cells in several physiological contexts and is driven by the immunoregulatory cytokine IL-27. Computational analysis identified the transcription factors PRDM1 and c-MAF as cooperative regulators of the co-inhibitory module, and this was validated experimentally. This molecular circuit underlies the co-expression of co-inhibitory receptors in T cells and identifies regulators of T cell function with the potential to control autoimmunity and tumour immunity.

PMID:
29899446
PMCID:
PMC6130914
DOI:
10.1038/s41586-018-0206-z
[Indexed for MEDLINE]
Free PMC Article

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