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

Author

Listed:
  • Calvin Law

    (Northwestern University
    Northwestern University
    Northwestern University
    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
    Northwestern University
    Northwestern University
    Northwestern University)

  • John Sowerby

    (Brigham and Women’s Hospital and Harvard Medical School)

  • Brandon Hancock

    (Northwestern University
    Northwestern University
    Northwestern University
    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
    Brigham and Women’s Hospital)

  • 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
    University of Colorado School of Medicine)

  • 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
    Northwestern University
    Northwestern University
    Northwestern University)

  • Deepak A. Rao

    (Brigham and Women’s Hospital and Harvard Medical School)

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.

Suggested Citation

  • Calvin Law & Vanessa Sue Wacleche & Ye Cao & Arundhati Pillai & John Sowerby & Brandon Hancock & Alice Horisberger & Sabrina Bracero & Viktoriya Skidanova & Zhihan Li & Ifeoluwakiisi Adejoorin & Eilis, 2024. "Interferon subverts an AHR–JUN axis to promote CXCL13+ T cells in lupus," Nature, Nature, vol. 631(8022), pages 857-866, July.
  • Handle: RePEc:nat:nature:v:631:y:2024:i:8022:d:10.1038_s41586-024-07627-2
    DOI: 10.1038/s41586-024-07627-2
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