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Interferon subverts an AHR-JUN axis to promote CXCL13+ T cells in lupus
Law C. et al.
Nature. 2024
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by abnormal interactions between T cells and B cells. This study focuses on the expansion of CXCL13+ T cells, particularly T follicular helper (TFH) and T peripheral helper (TPH) cells, which play central roles in B cell activation and disease progression. Although these cells produce CXCL13, the regulation of its production and the relationship between CXCL13+ T cells and other T cell subsets remain unclear. The authors identify a shift in CD4+ T cell phenotypes in SLE patients, with an increased frequency of PD-1+/ICOS+ CXCL13+ T cells and a decreased frequency of CD96hi IL-22+ T cells. Through CRISPR screens, they uncover the aryl hydrocarbon receptor (AHR) as a key negative regulator of CXCL13 production in T cells. Transcriptomic, epigenetic, and functional analyses show that AHR collaborates with the AP-1 family member JUN to inhibit the differentiation of CXCL13+ TPH/TFH cells and instead promote an IL-22+ phenotype. Type I interferon (IFN), a key driver of SLE, disrupts the AHR–JUN axis, promoting the production of CXCL13+ T cells and exacerbating the inflammatory response. These findings place CXCL13+ TPH/TFH cells on a polarization axis opposite to T helper 22 (TH22) cells, highlighting the AHR-JUN pathway as a crucial regulator of this polarization in lupus.
DOI: 10.1038/s41586-024-07627-2
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Nayer B. et al.
Nat Commun. 2024
Regulatory T cells (Tregs) are essential for tissue repair and regeneration. This study explores the potential of exogenous Tregs as a cell-based regenerative therapy. The researchers locally delivered Tregs to injured mouse bone, muscle, and skin, significantly enhancing tissue healing. The Tregs quickly adapted to the injury-specific microenvironment, upregulating genes involved in immunomodulation and tissue repair. They modulated monocytes/macrophages (Mo/MΦ), promoting an anti-inflammatory and pro-healing state through the secretion of interleukin (IL)-10. The regenerative effect was abolished when IL-10 was knocked out. Additionally, Tregs reduced the accumulation of neutrophils and cytotoxic T cells, as well as IFN-γ production, further attenuating inflammation. The study also demonstrated that both allogeneic and human Tregs could promote tissue healing, suggesting that exogenous Tregs could serve as a universal cell-based therapy for regenerative medicine.
DOI: 10.1038/s41467-024-51353-2
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