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

• 成果类型: Article
• 署名作者: 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.
• 署名单位: Northwestern University; Feinberg School of Medicine; Northwestern University; Feinberg School of Medicine; Northwestern University; Feinberg School of Medicine; Northwestern University; Northwestern University; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; AstraZeneca; AstraZeneca; Johnson & Johnson; Janssen Pharmaceuticals; Merck & Company; Merck & Company USA; University of Colorado System; University of Colorado Anschutz Medical Campus; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Northwestern University; Feinberg School of Medicine; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4379
• DOI: 10.1038/s41586-024-07627-2
• 发表日期: 2024-07-25
• 页码: 857-+
• 关键词: distinct; responses; differentiation; autoimmunity; anifrolumab; expression; signatures; il-22; il-17

摘要

Systemic lupus erythematosus (SLE) is prototypical autoimmune disease driven by pathological T cell-B cell interactions(1,2). Expansion of T follicular helper (T-FH) and T peripheral helper (T-PH) 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 CD96(hi) 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(+) T-PH/T-FH 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(+) T-PH/ T-FH 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.