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 Sowerby, Alice Horisberger, Sabrina Bracero, Viktoriya Skidanova, Zhihan J. Li, Ifeoluwakiisi Adejoorin, Eilish Dillon, Isaac J. Benque, Diana Pena Nunez, Diamon P. Simmons, Joshua Keegan, Lin Chen, Tina Baker, Phillip Z. Brohawn, Hussein Al-MossawiLing-Yang Hao, Brian Jones, Navin Rao, Yujie Qu, Stephen 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*, Deepak A. Rao*, Accelerating Medicines Partnership RA/SLE Network

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)857-866
Number of pages33
JournalNature
Volume631
DOIs
Publication statusPublished - 10 Jul 2024
  • Publisher Correction: Interferon subverts an AHR–JUN axis to promote CXCL13+ T cells in lupus

    Law, C., Wacleche, V. S., Cao, Y., Pillai, A., Sowerby, J., Sowerby, B., Horisberger, A., Bracero, S., Skidanova, V., Li, Z. J., Adejoorin, I., Dillon, E., Benque, I. J., Pena Nunez, D., Simmons, D. P., Keegan, J., Chen, L., Baker, T., Brohawn, P. Z., Al-Mossawi, H., & 16 othersHao, L-Y., Jones, B., Rao, N., Qu, Y., Alves, S., Jonsson, A. H., Shaw, K. S., Vleugels, R. A., Massarotti, E., Costenbader, K. H., Brenner, M. B., Lederer, J. A., Hultquist, J. F., Choi, J., Rao, D. A. & Accelerating Medicines Partnership RA/SLE Network, 26 Jul 2024, In: Nature. 631, 1 p.

    Research output: Contribution to journalComment/debatepeer-review

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