TY - JOUR
T1 - Deficient Activity of the Nuclease MRE11A Induces T Cell Aging and Promotes Arthritogenic Effector Functions in Patients with Rheumatoid Arthritis
AU - Li, Yinyin
AU - Shen, Yi
AU - Hohensinner, Philipp
AU - Ju, Jihang
AU - Wen, Zhenke
AU - Goodman, Stuart B.
AU - Zhang, Hui
AU - Goronzy, Jörg J.
AU - Weyand, Cornelia M.
N1 - Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/10/18
Y1 - 2016/10/18
N2 - 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, MRE11Alow T 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.
AB - 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, MRE11Alow T 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.
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U2 - 10.1016/j.immuni.2016.09.013
DO - 10.1016/j.immuni.2016.09.013
M3 - Article
C2 - 27742546
AN - SCOPUS:84994890342
SN - 1074-7613
VL - 45
SP - 903
EP - 916
JO - Immunity
JF - Immunity
IS - 4
ER -