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

Systemic lupus erythematosus (SLE) is prototypical autoimmune disease driven by pathological T cell–B cell interactions1,2. Expansion of T follicular helper (T_FH) and T peripheral helper (T_PH) cells, two T cell populations that provide help to B cells, is a prominent feature of SLE3,4. Human T_FH and T_PH 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 CD96^hi 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⁺ T_PH/T_FH 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⁺ T_PH/T_FH cells on a polarization axis opposite from T helper 22 (T_H22) cells and reveal AHR, JUN and interferon as key regulators of these divergent T cell states.Insufficient AHR activation has been suggested in SLE, and augmenting AHR activation therapeutically may prevent CXCL13⁺ T_PH/T_FH differentiation and the subsequent recruitment of B cells and formation of lymphoid aggregates in inflamed tissues. [ABSTRACT FROM AUTHOR]