Interferon subverts an AHR-JUN axis to promote CXCL13+ T cells in lupus.
Nature
; 631(8022): 857-866, 2024 Jul.
Article
em En
| MEDLINE
| ID: mdl-38987586
ABSTRACT
Systemic lupus erythematosus (SLE) is prototypical autoimmune disease driven by pathological T cell-B cell interactions1,2. Expansion of T follicular helper (TFH) and T peripheral helper (TPH) cells, two T cell populations that provide help to B cells, is a prominent feature of SLE3,4. Human TFH and TPH cells characteristically produce high levels of the B cell chemoattractant CXCL13 (refs. 5,6), 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 patients with SLE, 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, 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 T helper 22 (TH22) cells and reveal AHR, JUN and interferon as key regulators of these divergent T cell states.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Linfócitos T CD4-Positivos
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Interferon Tipo I
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Proteínas Proto-Oncogênicas c-jun
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Receptores de Hidrocarboneto Arílico
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Fatores de Transcrição Hélice-Alça-Hélice Básicos
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Quimiocina CXCL13
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Lúpus Eritematoso Sistêmico
Limite:
Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article