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| Status |
Public on Jul 08, 2024 |
| Title |
Interferon subverts an AHR-JUN axis to promote CXCL13+ T cells in lupus [AHR] |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
SLE is prototypical autoimmune disease driven by pathologic T cell-B cell interactions. Expansion of B cell-helper T cells including T follicular helper (Tfh) and T peripheral helper (Tph) cells is a prominent feature of systemic lupus erythematosus (SLE). Human Tfh and Tph cells characteristically produce high levels of the B cell chemoattractant CXCL135,6, yet regulation of T cell CXCL13 production and the relationship between CXCL13+ T cells and other T cell states remains unclear. Here, we identify an imbalance in CD4 T cell phenotypes in SLE patients, with expansion of PD-1+/ICOS+ CXCL13+ T cells and reduction of CD96hi IL-22+ T cells. Using CRISPR screens, we identify the aryl hydrocarbon receptor (AHR) as a potent negative regulator of CXCL13 production by human CD4 T cells. Transcriptomic, epigenetic, and functional studies demonstrate that AHR coordinates with AP-1 family member JUN to prevent CXCL13+ Tph/Tfh cell differentiation and promote an IL-22+ phenotype. Type I interferon (IFN), a pathogenic driver of SLE7, opposes AHR and JUN to promote T cell production of CXCL13. These results place CXCL13+ Tph/Tfh cells on a polarization axis opposite from Th22 cells and reveal AHR, JUN, and IFN as key regulators of these divergent T cell states.
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| Overall design |
Primary human CD4+ memory T cells nucleofected with either sgAHR or Non-targeting guide RNA were stimulated with CD3/CD28 dynabeads and AHR agonist (TCDD, 3nM) for 72 hours.
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| Contributor(s) |
Law C, Choi J, Rao DA |
| Citation(s) |
38987586 |
| |
| Submission date |
May 21, 2023 |
| Last update date |
Jul 17, 2024 |
| Contact name |
Calvin Law |
| E-mail(s) |
[email protected]
|
| Organization name |
Northwestern University
|
| Department |
Dermatology
|
| Lab |
Choi Lab
|
| Street address |
303 E Superior St Lurie 5-220
|
| City |
Chicago |
| State/province |
IL |
| ZIP/Postal code |
60611 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
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| Samples (12)
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| This SubSeries is part of SuperSeries: |
| GSE233050 |
Interferon subverts an AHR-JUN axis to promote CXCL13+ T cells in lupus |
|
| Relations |
| BioProject |
PRJNA974832 |
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