Interferon subverts an AHR–JUN axis to promote CXCL13+ T cells in lupus.

Autor: Law, Calvin, Wacleche, Vanessa Sue, Cao, Ye, Pillai, Arundhati, Sowerby, John, Hancock, Brandon, Horisberger, Alice, Bracero, Sabrina, Skidanova, Viktoriya, Li, Zhihan, Adejoorin, Ifeoluwakiisi, Dillon, Eilish, Benque, Isaac J., Nunez, Diana Pena, Simmons, Daimon P., Keegan, Joshua, Chen, Lin, Baker, Tina, Brohawn, Phillip Z., Al-Mossawi, Hussein
Zdroj: Nature; Jul2024, Vol. 631 Issue 8022, p857-866, 10p
Abstrakt: 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.Insufficient AHR activation has been suggested in SLE, and augmenting AHR activation therapeutically may prevent CXCL13+ TPH/TFH differentiation and the subsequent recruitment of B cells and formation of lymphoid aggregates in inflamed tissues. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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