title: Deficient Activity of the Nuclease MRE11A Induces T Cell Aging and Promotes Arthritogenic Effector Functions in Patients with Rheumatoid Arthritis.
abstract: Immune aging manifests with a combination of failing adaptive immunity and insufficiently restrained inflammation. In patients with rheumatoid arthritis (RA), T cell aging occurs prematurely, but the mechanisms involved and their contribution to tissue-destructive inflammation remain unclear. We found that RA CD4+T cells showed signs of aging during their primary immune responses and differentiated into tissue-invasive, proinflammatory effector cells. RA T cells had low expression of the double-strand-break repair nuclease MRE11A, leading to telomeric damage, juxtacentromeric heterochromatin unraveling, and senescence marker upregulation. Inhibition of MRE11A activity in healthy T cells induced the aging phenotype, whereas MRE11A overexpression in RA T cells reversed it. In human-synovium chimeric mice, MRE11AlowT cells were tissue-invasive and pro-arthritogenic, and MRE11A reconstitution mitigated synovitis. Our findings link premature T cell aging and tissue-invasiveness to telomere deprotection and heterochromatin unpacking, identifying MRE11A as a therapeutic target to combat immune aging and suppress dysregulated tissue inflammation.
authors.affiliation: Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Yinyin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Internal Medicine II/Cardiology, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Philipp
authors.initials: P
authors.lastname: Hohensinner
authors.affiliation: Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Jihang
authors.initials: J
authors.lastname: Ju
authors.affiliation: Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Zhenke
authors.initials: Z
authors.lastname: Wen
authors.affiliation: Department of Orthopedic Surgery and Bioengineering, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Stuart B
authors.initials: SB
authors.lastname: Goodman
authors.affiliation: Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Jörg J
authors.initials: JJ
authors.lastname: Goronzy
authors.affiliation: Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: cweyand@stanford.edu.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Weyand
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000276:immunology*; D004249:DNA Damage / Q000276:immunology; D004260:DNA Repair / Q000276:immunology; D004268:DNA-Binding Proteins / Q000276:immunology*; D003851:Deoxyribonucleases / Q000276:immunology*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D051379:Mice; D013585:Synovitis / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D016615:Telomere / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
chemical_list: D004268:DNA-Binding Proteins; D003851:Deoxyribonucleases