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

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Title: Interferon subverts an AHR–JUN axis to promote CXCL13+T cells in lupus
Authors: 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, Hao, Ling-Yang, Jones, Brian, Rao, Navin, Qu, Yujie, Alves, Stephen E., Jonsson, A. Helena, Shaw, Katharina S., Vleugels, Ruth Ann, Massarotti, Elena, Costenbader, Karen H., Brenner, Michael B., Lederer, James A., Hultquist, Judd F., Choi, Jaehyuk, Rao, Deepak A.
Source: Nature; July 2024, Vol. 631 Issue: 8022 p857-866, 10p
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 TFHand TPHcells 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 CD96hiIL-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/TFHcell 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/TFHcells 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.
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  Data: Interferon subverts an AHR–JUN axis to promote CXCL13+T cells in lupus
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  Data: Nature; July 2024, Vol. 631 Issue: 8022 p857-866, 10p
– Name: Abstract
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  Data: 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 TFHand TPHcells 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 CD96hiIL-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/TFHcell 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/TFHcells 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.
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