期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 128, 期 12, 页码 5222-5234出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI120216
关键词
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资金
- NIH [R01CA160433, R01HL119476, RO1CA225027, R01HL110907]
- Maryland Stem Cell Research Foundation
- Commonwealth Foundation
- Gary Williams Foundation
- S&R Foundation Kuno Award
- Turock Scholar Fund
- NATIONAL CANCER INSTITUTE [R01CA225027, R01CA160433] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL135062, R00HL113105, R01HL119476] Funding Source: NIH RePORTER
The mechanisms that drive T cell aging are not understood. We report that children and adult telomerase mutation carriers with short telomere length (TL) develop a T cell immunodeficiency that can manifest in the absence of bone marrow failure and causes life-threatening opportunistic infections. Mutation carriers shared T cell-aging phenotypes seen in adults 5 decades older, including depleted naive T cells, increased apoptosis, and restricted T cell repertoire. T cell receptor excision circles (TRECs) were also undetectable or low, suggesting that newborn screening may identify individuals with germline telomere maintenance defects. Telomerase-null mice with short TL showed defects throughout T cell development, including increased apoptosis of stimulated thymocytes, their intrathymic precursors, in addition to depleted hematopoietic reserves. When we examined the transcriptional programs of T cells from telomerase mutation carriers, we found they diverged from older adults with normal TL. Short telomere T cells upregulated DNA damage and intrinsic apoptosis pathways, while older adult T cells upregulated extrinsic apoptosis pathways and programmed cell death 1 (PD-1) expression. T cells from mice with short TL also showed an active DNA-damage response, in contrast with old WT mice, despite their shared propensity to apoptosis. Our data suggest there are TL-dependent and TL-independent mechanisms that differentially contribute to distinct molecular programs of T cell apoptosis with aging.
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