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

Calvin Law, Vanessa Sue Wacleche, Ye Cao, Arundhati Pillai, John Sowerby, Brandon Hancock, Alice Horisberger, Sabrina Bracero, Viktoriya Skidanova, Zhihan Li, Ifeoluwakiisi Adejoorin, Eilish Dillon, Isaac J. Benque, Diana Pena Nunez, Daimon P. Simmons, Joshua Keegan, Lin Chen, Tina Baker, Phillip Z. Brohawn, Hussein Al-Mossawi, Ling-Yang Hao, Brian Jones, Navin Rao, Yujie Qu, Stephen E. Alves, A. Helena Jonsson, Katharina S. Shaw, Ruth Ann Vleugels, Elena Massarotti, Karen H. Costenbader, Michael B. Brenner, James A. Lederer, Judd F. Hultquist, Jaehyuk Choi () and Deepak A. Rao ()
Additional contact information
Calvin Law: Northwestern University
Vanessa Sue Wacleche: Brigham and Women’s Hospital and Harvard Medical School
Ye Cao: Brigham and Women’s Hospital and Harvard Medical School
Arundhati Pillai: Northwestern University
John Sowerby: Brigham and Women’s Hospital and Harvard Medical School
Brandon Hancock: Northwestern University
Alice Horisberger: Brigham and Women’s Hospital and Harvard Medical School
Sabrina Bracero: Brigham and Women’s Hospital and Harvard Medical School
Viktoriya Skidanova: Brigham and Women’s Hospital and Harvard Medical School
Zhihan Li: Brigham and Women’s Hospital and Harvard Medical School
Ifeoluwakiisi Adejoorin: Brigham and Women’s Hospital and Harvard Medical School
Eilish Dillon: Brigham and Women’s Hospital and Harvard Medical School
Isaac J. Benque: Brigham and Women’s Hospital and Harvard Medical School
Diana Pena Nunez: Brigham and Women’s Hospital and Harvard Medical School
Daimon P. Simmons: Brigham and Women’s Hospital and Harvard Medical School
Joshua Keegan: Brigham and Women’s Hospital
Lin Chen: Brigham and Women’s Hospital and Harvard Medical School
Tina Baker: AstraZeneca
Phillip Z. Brohawn: AstraZeneca
Hussein Al-Mossawi: Late Respiratory and Immunology
Ling-Yang Hao: Janssen Research & Development
Brian Jones: Janssen Research & Development
Navin Rao: Janssen Research & Development
Yujie Qu: Inc.
Stephen E. Alves: Inc.
A. Helena Jonsson: Brigham and Women’s Hospital and Harvard Medical School
Katharina S. Shaw: Boston
Ruth Ann Vleugels: Boston
Elena Massarotti: Brigham and Women’s Hospital and Harvard Medical School
Karen H. Costenbader: Brigham and Women’s Hospital and Harvard Medical School
Michael B. Brenner: Brigham and Women’s Hospital and Harvard Medical School
James A. Lederer: Brigham and Women’s Hospital
Judd F. Hultquist: Northwestern University
Jaehyuk Choi: Northwestern University
Deepak A. Rao: Brigham and Women’s Hospital and Harvard Medical School

Nature, 2024, vol. 631, issue 8022, 857-866

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-07627-2

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