Abstract Text: Expansion of B cell helper-T cells, including T follicular helper (Tfh) and T peripheral helper cells (Tph) is a prominent feature of systemic lupus erythematosus (SLE), an autoimmune disease with broad autoantibody production. Human Tfh and Tph cells highly express the B cell chemoattractant CXCL13; however, regulation of CXCL13 production by T cells remains largely unknown. Here, mass cytometry immunophenotyping revealed a marked imbalance in CD4 T cell phenotypes in SLE patients, with expansion of CXCL13+ Tfh/Tph cells and specific reduction of CD96hi IL-22+ T cells. We hypothesized that a common regulator might drive this skewed balance. Using CRISPR screens of human CD4 T cells, we identified the transcription factor aryl hydrocarbon receptor (AHR) as a central regulator of an axis of T cell polarization with CXCL13+ and IL-22+ states at opposing ends. Transcriptomic, epigenetic, CUT&RUN, and functional studies demonstrated that 1) AHR activation drives T cells away from a CXCL13+ phenotype and towards an IL-22+ phenotype, and 2) AHR engages the AP-1 family member JUN to regulate CXCL13- and IL-22-associated phenotypes. Treatment of T cells from SLE patients with an AHR agonist reduced the frequency of PD-1+ Tph cells. In contrast, type I interferon (IFN-I), a central mediator in SLE, represses AHR activation in T cells and synergizes with AHR inhibition to boost CXCL13 production and promote a Tph cell phenotype. These results reveal AHR, JUN, and IFN-I as regulators of a previously unrecognized CXCL13 <—> IL-22 polarization axis and highlight an imbalance of this axis in SLE.
