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.
Adipose tissue harbors pathogenic T cells in obesity that exacerbate inflammatory arthritis
https://orcid.org/0000-0001-5305-3323
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https://orcid.org/0000-0002-9558-2474
https://orcid.org/0000-0003-1864-0594
https://orcid.org/0009-0008-6072-5077
https://orcid.org/0000-0002-5642-0608
https://orcid.org/0000-0002-4273-4681
https://orcid.org/0000-0002-2126-3702
https://orcid.org/0000-0001-6202-8445
Disclosures: L. Lynch reported personal fees from Science Advances and Faeth Therapeutics outside the submitted work. P.A. Nigrovic reported grants from BMS, personal fees from Merck, Pfizer, Novartis, Sobi, Fresh Tracks Bio, Apollo, Alkermes, Century Therapeutics, Monte Rosa, and Simcere, and other from Edelweiss Immune outside the submitted work. M.B. Brenner reported personal fees from AbbVie and Moderna, other from Mestag Therapeutic, and grants from Johnson & Johnson and Ono Pharma outside the submitted work; in addition, M.B. Brenner had a patent to Granzyme K inflammation pending. No other disclosures were reported.
A.H. Jonsson’s current affiliation is Division of Rheumatology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
N.M. LaMarche’s current affiliation is Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
N.M. LaMarche’s current affiliation is Yale Cancer Biology Institute, West Haven, CT, USA.
W.V. Trim’s current affiliation is Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
L. Lynch’s current affiliation is Ludwig Cancer Research Institute, Princeton University, Princeton, NJ, USA.
