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 - Funding Information:
This work was supported by grants from the National Institutes of Health (R01 AR042547, R01 HL117913, R01 AI108906, P01 HL129941, R01 AI108891, R01AR055650, R01AR063717, R01 AG045779, and I01 BX001669) and from the Govenar Discovery Fund.
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 -