美国布里格姆妇女医院和哈佛医学院Deepak A. Rao和美国西北大学Jaehyuk Choi团队共同合作，近期取得重要工作进展。他们研究提出，干扰素破坏AHR-JUN轴促进红斑狼疮中CXCL13⁺ T细胞。相关研究成果2024年7月10日在线发表于《自然》杂志上。

据介绍，系统性红斑狼疮（SLE）是由病理性T细胞-B细胞相互作用引起的典型自身免疫性疾病。T滤泡辅助细胞（TFH）和T外周辅助细胞（TPH）这两种为B细胞提供帮助的T细胞群的扩增是SLE的一个显著特征。人TFH和TPH细胞特征性地产生高水平的B细胞趋化剂CXCL13，但T细胞CXCL13产生的调控以及CXCL13⁺ T细胞与其他T细胞状态之间的关系尚不清楚。

研究人员发现SLE患者CD4⁺ T细胞表型不平衡，PD-1⁺/ICOS⁺ CXCL13⁺ T细胞扩增，CD96^hi IL-22⁺ T细胞减少。使用CRISPR筛选，研究人员鉴定出芳基烃受体（AHR）是人类CD4⁺ T细胞产生CXCL13的强效负调节因子。转录组学、表观遗传和功能研究表明，AHR与AP-1家族成员JUN协同作用，阻止CXCL13⁺ T_PH/T_FH细胞分化，促进IL-22⁺表型。I型干扰素是SLE7的致病驱动因素，它对抗AHR和JUN，促进T细胞产生CXCL13。

总之，这些结果将CXCL13⁺ TPH/TFH细胞置于与T辅助22（TH22）细胞相反的极化轴上，并揭示了AHR、JUN和干扰素是这些不同T细胞状态的关键调节因子。

附：英文原文

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

Author: 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.

Issue&Volume: 2024-07-10

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.

DOI: 10.1038/s41586-024-07627-2

Source: https://www.nature.com/articles/s41586-024-07627-2