Essential Roles of the Transcription Factor NR4A1 in Regulatory T Cell Differentiation under the Influence of Immunosuppressants
Abstract
Calcineurin inhibitors (CNIs), used as immunosuppressants, have revolutionized transplantation medicine with their strong suppressive activity on alloreactive T lymphocytes; however, they may also cause various adverse effects, including an increased risk for infection and nephrotoxicity. Regulatory T (Treg) cells can complement the deleterious side effects of CNIs with their effective Ag-specific suppressive activities. However, several studies have shown that CNIs suppress Treg cell differentiation. Therefore, an understanding of the mechanisms by which CNIs suppress Treg cell differentiation, as well as an approach for promoting the differentiation of Treg cells in the presence of CNIs, has significant clinical value. In this article, we report that the nuclear orphan receptor Nr4a1 plays a pivotal role in Treg cell differentiation in the presence of CNIs. Unlike that of its family members, Nr4a2 and Nr4a3, the expression of Nr4a1 was not suppressed by CNI treatment, thereby mediating Treg cell differentiation in the presence of CNIs. In a mouse allogeneic graft-versus-host disease model, Nr4a1 mediated tolerance by promoting Treg cell differentiation in mice administered cyclosporine A, prolonging the survival of recipients. Furthermore, activation of Nr4a1 via its agonist partially restored Treg cell differentiation, which was suppressed by cyclosporine A treatment. Finally, we found that the rs2701129 single-nucleotide polymorphism, which was shown to downregulate NR4A1…
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The identified TFs (FOXK2 and NR4A1) have important roles in naive CD4+ T cell response upon TCR stimulation.
“Other studies have also shown that FOXK2 affects the activation of T lymphocytes77,78 and revealed the essential roles of NR4A1 in regulatory T cell differentiation79,80, suggesting that the identified TFs have important roles in naive CD4+ T cell response upon TCR stimulation.”
From Inferring gene regulatory networks from single-cell multiome data using atlas-scale external data (2025) · cites this paper as [79]
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- Authors
- Sekiya, T., Kasahara, H., Takemura, R., Fujita, S., Kato, J., Doki, N., Katayama, Y., Ozawa, Y., Takada, S., Eto, T., Fukuda, T., Ichinohe, T., Takanashi, M., Onizuka, M., Atsuta, Y., Okamoto, S., Yoshimura, A., Takaki, S., & Mori, T.
- Affiliations
- National Center for Global Health and Medicine (JP)
- Keio University (JP)
- Keio University Hospital (JP)
- Tokyo Metropolitan Komagome Hospital (JP)
- Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital (JP)
- Japanese Red Cross Nagoya Daiichi Hospital (JP)
- Gunma Saiseikai Maebashi Hospital (JP)
- Hamanomachi Hospital (JP)
- National Cancer Center Hospital (JP)
- Hiroshima University (JP)
- Japanese Red Cross Society, Japan (JP)
- Tokai University (JP)
- Aichi Medical University (JP)
- Department of Immune Regulation, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine , Ichikawa, Chiba,
- Tokyo Medical and Dental University (JP)
- Corresponding author
- Sekiya, Takashi
- Katayama, Yuta
- Onizuka, Makoto
- ORCID
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2022-05-01
- Volume
- 208
- Issue
- 9
- Pages
- 2122-2130
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W4224951318
- Cited by
- 16
- References
- 53
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 6 · 2023: 4
- FWCI
- 1.34
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- MEXT | Japan Society for the Promotion of Science (21H02756, 21K19393, 19H04822, 20H04958, JP17H06175)
- Takeda Science Foundation
- SENSHIN Medical Research Foundation
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Grants for National Center for Global Health and Medicine (20A1005)
- Japan Agency for Medical Research and Development (JP19gm1110009)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- Nur77, Treg differentiation, calcineurin inhibitors, cyclosporine, immunosuppressants, graft-versus-host disease, hematopoietic stem cell transplantation, orphan nuclear receptor, alloreactive T cells, immune tolerance
- MeSH terms
- Animals, Cell Differentiation, Graft vs Host Disease, Humans, Immunosuppressive Agents, Transcription Factors, Cyclosporine, T-Lymphocytes, Regulatory, Mice, Nuclear Receptor Subfamily 4, Group A, Member 1
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