Faust Heather J, Chang Margaret H, Jonsson A Helena, Theisen Erin, LaMarche Nelson M, Trim William V, Lynch Lydia, Nigrovic Peter A, Brenner Michael B
Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Division of Immunology, Boston Children's Hospital, Boston, MA, USA.
J Exp Med. 2025 Sep 1;222(9). doi: 10.1084/jem.20240677. Epub 2025 Jul 7.
Obesity worsens inflammatory arthritis severity, even in non-load-bearing joints, but the mechanism is unknown. Here, we show that there is an immunological mechanism mediated by T cells in adipose tissue. Using an antigen-induced arthritis model with trackable, arthritis-inducing CD8+ OT-I T cells, we found that OT-I T cells home to visceral adipose tissue (VAT) and expand there in the obese high-fat diet (HFD) context. Transplant of VAT from arthritic mice increased arthritis severity in naïve recipient mice and was ameliorated by CD8 T cell depletion. Bulk RNA sequencing identified pro-inflammatory changes to OT-I T cells in VAT characterized by increased IFN α and γ signaling after HFD. Intraperitoneal injection of IFNα, but not IFNγ, expanded CD8 T cell numbers in VAT. HFD-induced expansion of VAT CD8 T cells was ameliorated with global Ifnar1 deletion, and importantly, genetic deletion of Ifnar1 in T cells decreased arthritis severity in obese mice. These results provide a mechanistic explanation of how obesity worsens autoimmunity.
肥胖会加重炎症性关节炎的严重程度,即使在非负重关节也是如此,但其机制尚不清楚。在此,我们表明脂肪组织中存在一种由T细胞介导的免疫机制。使用具有可追踪的、诱导关节炎的CD8+ OT-I T细胞的抗原诱导性关节炎模型,我们发现OT-I T细胞归巢至内脏脂肪组织(VAT)并在肥胖高脂饮食(HFD)背景下在那里扩增。来自关节炎小鼠的VAT移植增加了未接触过抗原的受体小鼠的关节炎严重程度,并且通过CD8 T细胞耗竭得到改善。大量RNA测序确定了VAT中OT-I T细胞的促炎变化,其特征是HFD后IFNα和γ信号增加。腹腔注射IFNα而非IFNγ可增加VAT中CD8 T细胞数量。全球Ifnar1缺失改善了HFD诱导的VAT CD8 T细胞扩增,重要的是,T细胞中Ifnar1的基因缺失降低了肥胖小鼠的关节炎严重程度。这些结果为肥胖如何加重自身免疫提供了一种机制解释。