Nr4a1 and Nr4a3 redundantly control clonal deletion and contribute to an anergy-like transcriptome in auto-reactive thymocytes to impose tolerance in mice
Abstract The Nr4a nuclear hormone receptors are transcriptionally upregulated in response to antigen recognition by the T cell receptor (TCR) in the thymus and are implicated in clonal deletion, but the mechanisms by which they operate are not clear. Moreover, their role in central tolerance is obsc...
Saved in:
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-01-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-55839-5 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832594538003169280 |
|---|---|
| author | Hailyn V. Nielsen Letitia Yang James L. Mueller Alexander J. Ritter Ryosuke Hiwa Irina Proekt Elze Rackaityte Dominik Aylard Mansi Gupta Christopher D. Scharer Mark S. Anderson Byron B. Au-Yeung Julie Zikherman |
| author_facet | Hailyn V. Nielsen Letitia Yang James L. Mueller Alexander J. Ritter Ryosuke Hiwa Irina Proekt Elze Rackaityte Dominik Aylard Mansi Gupta Christopher D. Scharer Mark S. Anderson Byron B. Au-Yeung Julie Zikherman |
| author_sort | Hailyn V. Nielsen |
| collection | DOAJ |
| description | Abstract The Nr4a nuclear hormone receptors are transcriptionally upregulated in response to antigen recognition by the T cell receptor (TCR) in the thymus and are implicated in clonal deletion, but the mechanisms by which they operate are not clear. Moreover, their role in central tolerance is obscured by redundancy among the Nr4a family members and by their reported functions in Treg generation and maintenance. Here we take advantage of competitive bone marrow chimeras and the OT-II/RIPmOVA model to show that Nr4a1 and Nr4a3 are essential for the upregulation of Bcl2l11/BIM and thymic clonal deletion by self-antigen. Importantly, thymocytes lacking Nr4a1/3 acquire an anergy-like signature after escaping clonal deletion and Treg lineage diversion. We further show that the Nr4a family helps mediate a broad transcriptional program in self-reactive thymocytes that resembles anergy and may operate at the margins of canonical thymic tolerance mechanisms to restrain self-reactive T cells after thymic egress. |
| format | Article |
| id | doaj-art-29d83af1ef7b4d09b87bf947b714cc14 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-29d83af1ef7b4d09b87bf947b714cc142025-01-19T12:31:09ZengNature PortfolioNature Communications2041-17232025-01-0116112210.1038/s41467-025-55839-5Nr4a1 and Nr4a3 redundantly control clonal deletion and contribute to an anergy-like transcriptome in auto-reactive thymocytes to impose tolerance in miceHailyn V. Nielsen0Letitia Yang1James L. Mueller2Alexander J. Ritter3Ryosuke Hiwa4Irina Proekt5Elze Rackaityte6Dominik Aylard7Mansi Gupta8Christopher D. Scharer9Mark S. Anderson10Byron B. Au-Yeung11Julie Zikherman12Division of Rheumatology, Rosalind Russell and Ephraim P. Engleman Arthritis Research Center, Department of Medicine, University of CaliforniaBiomedical Sciences Graduate Program, University of CaliforniaDivision of Rheumatology, Rosalind Russell and Ephraim P. Engleman Arthritis Research Center, Department of Medicine, University of CaliforniaDivision of Rheumatology, Rosalind Russell and Ephraim P. Engleman Arthritis Research Center, Department of Medicine, University of CaliforniaDepartment of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-kuDiabetes Center, Department of Medicine, University of CaliforniaDepartment of Biochemistry and Biophysics, University of CaliforniaDepartment of Molecular & Cell Biology, University of CaliforniaDepartment of Microbiology and Immunology, Emory UniversityDepartment of Microbiology and Immunology, Emory UniversityDiabetes Center, Department of Medicine, University of CaliforniaDivision of Immunology, Lowance Center for Human Immunology, Department of Medicine, Emory UniversityDivision of Rheumatology, Rosalind Russell and Ephraim P. Engleman Arthritis Research Center, Department of Medicine, University of CaliforniaAbstract The Nr4a nuclear hormone receptors are transcriptionally upregulated in response to antigen recognition by the T cell receptor (TCR) in the thymus and are implicated in clonal deletion, but the mechanisms by which they operate are not clear. Moreover, their role in central tolerance is obscured by redundancy among the Nr4a family members and by their reported functions in Treg generation and maintenance. Here we take advantage of competitive bone marrow chimeras and the OT-II/RIPmOVA model to show that Nr4a1 and Nr4a3 are essential for the upregulation of Bcl2l11/BIM and thymic clonal deletion by self-antigen. Importantly, thymocytes lacking Nr4a1/3 acquire an anergy-like signature after escaping clonal deletion and Treg lineage diversion. We further show that the Nr4a family helps mediate a broad transcriptional program in self-reactive thymocytes that resembles anergy and may operate at the margins of canonical thymic tolerance mechanisms to restrain self-reactive T cells after thymic egress.https://doi.org/10.1038/s41467-025-55839-5 |
| spellingShingle | Hailyn V. Nielsen Letitia Yang James L. Mueller Alexander J. Ritter Ryosuke Hiwa Irina Proekt Elze Rackaityte Dominik Aylard Mansi Gupta Christopher D. Scharer Mark S. Anderson Byron B. Au-Yeung Julie Zikherman Nr4a1 and Nr4a3 redundantly control clonal deletion and contribute to an anergy-like transcriptome in auto-reactive thymocytes to impose tolerance in mice Nature Communications |
| title | Nr4a1 and Nr4a3 redundantly control clonal deletion and contribute to an anergy-like transcriptome in auto-reactive thymocytes to impose tolerance in mice |
| title_full | Nr4a1 and Nr4a3 redundantly control clonal deletion and contribute to an anergy-like transcriptome in auto-reactive thymocytes to impose tolerance in mice |
| title_fullStr | Nr4a1 and Nr4a3 redundantly control clonal deletion and contribute to an anergy-like transcriptome in auto-reactive thymocytes to impose tolerance in mice |
| title_full_unstemmed | Nr4a1 and Nr4a3 redundantly control clonal deletion and contribute to an anergy-like transcriptome in auto-reactive thymocytes to impose tolerance in mice |
| title_short | Nr4a1 and Nr4a3 redundantly control clonal deletion and contribute to an anergy-like transcriptome in auto-reactive thymocytes to impose tolerance in mice |
| title_sort | nr4a1 and nr4a3 redundantly control clonal deletion and contribute to an anergy like transcriptome in auto reactive thymocytes to impose tolerance in mice |
| url | https://doi.org/10.1038/s41467-025-55839-5 |
| work_keys_str_mv | AT hailynvnielsen nr4a1andnr4a3redundantlycontrolclonaldeletionandcontributetoananergyliketranscriptomeinautoreactivethymocytestoimposetoleranceinmice AT letitiayang nr4a1andnr4a3redundantlycontrolclonaldeletionandcontributetoananergyliketranscriptomeinautoreactivethymocytestoimposetoleranceinmice AT jameslmueller nr4a1andnr4a3redundantlycontrolclonaldeletionandcontributetoananergyliketranscriptomeinautoreactivethymocytestoimposetoleranceinmice AT alexanderjritter nr4a1andnr4a3redundantlycontrolclonaldeletionandcontributetoananergyliketranscriptomeinautoreactivethymocytestoimposetoleranceinmice AT ryosukehiwa nr4a1andnr4a3redundantlycontrolclonaldeletionandcontributetoananergyliketranscriptomeinautoreactivethymocytestoimposetoleranceinmice AT irinaproekt nr4a1andnr4a3redundantlycontrolclonaldeletionandcontributetoananergyliketranscriptomeinautoreactivethymocytestoimposetoleranceinmice AT elzerackaityte nr4a1andnr4a3redundantlycontrolclonaldeletionandcontributetoananergyliketranscriptomeinautoreactivethymocytestoimposetoleranceinmice AT dominikaylard nr4a1andnr4a3redundantlycontrolclonaldeletionandcontributetoananergyliketranscriptomeinautoreactivethymocytestoimposetoleranceinmice AT mansigupta nr4a1andnr4a3redundantlycontrolclonaldeletionandcontributetoananergyliketranscriptomeinautoreactivethymocytestoimposetoleranceinmice AT christopherdscharer nr4a1andnr4a3redundantlycontrolclonaldeletionandcontributetoananergyliketranscriptomeinautoreactivethymocytestoimposetoleranceinmice AT marksanderson nr4a1andnr4a3redundantlycontrolclonaldeletionandcontributetoananergyliketranscriptomeinautoreactivethymocytestoimposetoleranceinmice AT byronbauyeung nr4a1andnr4a3redundantlycontrolclonaldeletionandcontributetoananergyliketranscriptomeinautoreactivethymocytestoimposetoleranceinmice AT juliezikherman nr4a1andnr4a3redundantlycontrolclonaldeletionandcontributetoananergyliketranscriptomeinautoreactivethymocytestoimposetoleranceinmice |