Induction and transcriptional regulation of the co-inhibitory gene module in T cells
Open accessAbstract
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 cancer 1,2. 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.
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The exhausted subset overexpressed Lag3, Tbc1d4, Sostdc1, and Tnfsf8.
“cells with an exhaustion signature (denoted exhausted, fig. S3B) overexpressing the Lag3, Tbc1d4, Sostdc1, and Tnfsf8 genes (22, 31)”
From Aging promotes reorganization of the CD4 T cell landscape toward extreme regulatory and effector phenotypes (2019) · cites this paper as [22]
Genes up-regulated in old cells presented a mix of inflammatory (e.g., S100a4, S100a11, Ccl5) and regulatory (e.g., Maf, Ikzf2, Tnfrsf4) signatures, as well as exhaustion markers (e.g., Lag3, Tnfsf8).
“genes up-regulated in old cells presented a mix of inflammatory (e.g., S100a4, S100a11, and Ccl5 genes) and regulatory (e.g., Maf, Ikzf2, and Tnfrsf4 genes) signatures (21), as well as exhaustion markers [e.g., Lag3 and Tnfsf8 genes (22); Fig. 1E and Materials and Methods].”
From Aging promotes reorganization of the CD4 T cell landscape toward extreme regulatory and effector phenotypes (2019) · cites this paper as [22]
RECs exhibited an active Prdm1 regulon, suggesting a certain degree of exhaustion.
“The RECs exhibited an active Prdm1 regulon, suggesting a certain degree of exhaustion in these subsets (22).”
From Aging promotes reorganization of the CD4 T cell landscape toward extreme regulatory and effector phenotypes (2019) · cites this paper as [22]
Exhausted cells expressed relatively high levels of coinhibitory genes Cd200, Lag3, and Pdcd1, as well as genes related to cellular oxidative stress Hif1a and Tbc1d4, compared to TEMs.
“the exhausted cells expressed relatively high levels of coinhibitory genes [e.g., Cd200, Lag3, and Pdcd1 (22)], as well as genes related to cellular oxidative stress [e.g., Hif1a and Tbc1d4 (37); Fig. 3B]”
From Aging promotes reorganization of the CD4 T cell landscape toward extreme regulatory and effector phenotypes (2019) · cites this paper as [22]
Selective IL-23 inhibitors (tildrakizumab, risankizumab, guselkumab) targeting IL-23 p19 are more effective than TNF inhibitors and IL-23/IL-12 inhibitors.
“More recently, selective IL-23 inhibitors (tildrakizumab, risankizumab, and guselkumab) that specifically target the IL-23 p19 subunit were found to be more effective than TNF inhibitors [137] and IL-23/IL-12 inhibitors [28, 138].”
From TH17 cell heterogeneity and its role in tissue inflammation (2023) · cites this paper as [138]
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- Authors
- Chihara, N., Madi, A., Kondo, T., Zhang, H., Acharya, N., Singer, M., Nyman, J., Marjanovic, N. D., Kowalczyk, M. S., Wang, C., Kurtulus, S., Law, T., Etminan, Y., Nevin, J., Buckley, C. D., Burkett, P. R., Buenrostro, J. D., Rozenblatt-Rosen, O., Anderson, A. C., Regev, A., & Kuchroo, V. K.
- Affiliations
- Brigham and Women's Hospital (US)
- Broad Institute (US)
- Queen Elizabeth Hospital Birmingham (GB)
- Corresponding author
- Anderson, Ana C.
- Regev, Aviv
- Kuchroo, Vijay K.
- ORCID
- Venue
- Nature
- Published
- 2018-06
- Volume
- 558
- Issue
- 7710
- Pages
- 454-459
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6130914
- OpenAlex
- W2808421749
- Cited by
- 438
- References
- 38
- Citations by year
- 2026: 17 · 2025: 49 · 2024: 59 · 2023: 59 · 2022: 64 · 2021: 59 · 2020: 69 · 2019: 46 · 2018: 16
- FWCI
- 20.42
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion, other-oa)
- Funders
- Howard Hughes Medical Institute
- American Cancer Society
- Melanoma Research Alliance
- Broad Institute
- National Institute for Health and Care Research (NF-SI-0617-10128)
- National Institutes of Health (5rm1hg006193-10)
- Klarman Cell Observatory, Broad Institute
- Japan Society for the Promotion of Science (18K15453)
- National Human Genome Research Institute (RM1‐HG006193)
- National Cancer Institute (R01CA187975)
- National Institute of Allergy and Infectious Diseases (K08AI123516, P01AI073748, P01AI056299, P01AI039671)
- National Institute of Neurological Disorders and Stroke (R01NS045937)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- co-inhibitory receptors, T cell exhaustion, CTLA-4, PD-1, TIM-3, LAG-3, TIGIT, protein C receptor, podoplanin, IL-27, Blimp-1, c-Maf, transcriptional regulation, CD4+ T cells, CD8+ T cells, autoimmunity, tumour immunity, single-cell expression profiling
- MeSH terms
- Positive Regulatory Domain I-Binding Factor 1, Animals, Female, Immune Tolerance, Male, Melanoma, Mice, Inbred C57BL, Receptors, Cell Surface, Transcription, Genetic, Reproducibility of Results, CD4-Positive T-Lymphocytes, Lymphocytes, Tumor-Infiltrating, Mice, Knockout, CD8-Positive T-Lymphocytes, Proto-Oncogene Proteins c-maf, Mice, Gene Regulatory Networks, Interleukin-27
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