Systemic lupus erythematosus (SLE) is characterized by increased frequencies of autoreactive B cells and T cells, resulting in the production of autoantibodies. In Nature, Law et al. show type I interferons (IFNs), a hallmark cytokine associated with SLE pathogenesis, skew the polarization of circulating CD4+ T cells towards CXCL13-expressing T peripheral helper (TPH) cells that can recruit B cells into affected tissues to promote local autoantibody production. Multi-OMIC analyses of CD4+ T cells from individuals with SLE and healthy donors identified an expansion of PD-1+ICOS+CXCL13+ TPH cells and reduced frequencies of CD96+ T helper cells expressing IL-22 in their SLE cohort. CRISPR-mediated mutagenesis identified aryl hydrocarbon receptor (AHR) as a transcription factor that negatively regulates TGFβ-induced CXCL13, PD-1 and ICOS expression in CD4+ T cells; conversely, loss of AHR reduces IL-22 and CD96 expression. Agonist ligands of AHR induced opposite effects in activated CD4+ TFH cells. Furthermore, ATAC-seq and transcriptomic profiling of CD4+ T cells showed that AHR coordinates with the AP-1 transcription factor JUN to regulate CXCL13 and IL22 gene expression. However, type I IFNs interfere with the AHR–JUN regulatory axis by decreasing the abundance of JUN protein, resulting in increased CXCL13 production. These findings indicate that type I IFN signaling alters normal gene regulatory pathways in CD4+ T cells that can promote aberrant collaboration between T cells and B cells in peripheral tissues and contribute to the pathogenesis of autoimmune diseases.
Original reference: Nature https://doi.org/10.1038/s41586-024-07627-2 (2024)
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