TY - JOUR
T1 - Interferon subverts an AHR–JUN axis to promote CXCL13+ T cells in lupus
AU - Law, Calvin
AU - Wacleche, Vanessa Sue
AU - Cao, Ye
AU - Pillai, Arundhati
AU - Sowerby, John
AU - Sowerby, Brandon
AU - Horisberger, Alice
AU - Bracero, Sabrina
AU - Skidanova, Viktoriya
AU - Li, Zhihan J.
AU - Adejoorin, Ifeoluwakiisi
AU - Dillon, Eilish
AU - Benque, Isaac J.
AU - Pena Nunez, Diana
AU - Simmons, Diamon P.
AU - Keegan, Joshua
AU - Chen, Lin
AU - Baker, Tina
AU - Brohawn, Phillip Z.
AU - Al-Mossawi, Hussein
AU - Hao, Ling-Yang
AU - Jones, Brian
AU - Rao, Navin
AU - Qu, Yujie
AU - Alves, Stephen
AU - Jonsson, A. Helena
AU - Shaw, Katharina S.
AU - Vleugels, Ruth Ann
AU - Massarotti, Elena
AU - Costenbader, Karen H.
AU - Brenner, Michael B.
AU - Lederer, James A.
AU - Hultquist, Judd F.
AU - Choi, Jaehyuk
AU - Rao, Deepak A.
AU - Accelerating Medicines Partnership RA/SLE Network
AU - Filer, Andrew
AU - Carr, Hayley
AU - Maybury, Mark
AU - Nayar, Saba
AU - Raza, Karim
AU - Sahbudin, Ilfita
AU - Scheel-Toellner, Dagmar
PY - 2024/7/10
Y1 - 2024/7/10
N2 - 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.
AB - 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.
U2 - 10.1038/s41586-024-07627-2
DO - 10.1038/s41586-024-07627-2
M3 - Article
SN - 0028-0836
VL - 631
SP - 857
EP - 866
JO - Nature
JF - Nature
ER -