期刊
IMMUNITY
卷 45, 期 4, 页码 903-916出版社
CELL PRESS
DOI: 10.1016/j.immuni.2016.09.013
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资金
- National Institutes of Health [R01 AR042547, R01 HL117913, R01 AI108906, P01 HL129941, R01 AI108891, R01AR055650, R01AR063717, R01 AG045779, I01 BX001669]
- Govenar Discovery Fund
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 tissuedestructive 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 doublestrand- 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, MRE11A (low) 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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