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 interactions. Expansion of T follicular helper (T) and T peripheral helper (T) cells, two T cell populations that provide help to B cells, is a prominent feature of SLE. Human T and T cells characteristically produce high levels of the B cell chemoattractant CXCL13 (refs. ), 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 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/T cell differentiation and promote an IL-22 phenotype. Type I interferon, a pathogenic driver of SLE, opposes AHR and JUN to promote T cell production of CXCL13. These results place CXCL13 T/T cells on a polarization axis opposite from T helper 22 (T22) cells and reveal AHR, JUN and interferon as key regulators of these divergent T cell states.