Journal article
Short telomere syndromes cause a primary T cell immunodeficiency
The Journal of clinical investigation, Vol.128(12), pp.5222-5234
12/03/2018
DOI: 10.1172/JCI120216
PMCID: PMC6264634
PMID: 30179220
Abstract
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.
Details
- Title: Subtitle
- Short telomere syndromes cause a primary T cell immunodeficiency
- Creators
- Christa L Wagner - Department of Oncology and.Vidya Sagar Hanumanthu - Department of Oncology and.C. Conover Talbot - Johns Hopkins University School of MedicineRoshini S Abraham - Mayo ClinicDavid Hamm - Adaptive BiotechnologiesDustin L Gable - Department of Oncology and.Christopher G Kanakry - Department of Oncology and.Carolyn D Applegate - McKusick-Nathans Institute of Genetic Medicine.Janet Siliciano - Department of Medicine.J. Brooks Jackson - Department of Pathology.Stephen Desiderio - Johns Hopkins University School of MedicineJonathan K Alder - Department of Oncology and.Leo Luznik - Department of Oncology and.Mary Armanios - Department of Oncology and.
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.128(12), pp.5222-5234
- Publisher
- American Society for Clinical Investigation
- DOI
- 10.1172/JCI120216
- PMID
- 30179220
- PMCID
- PMC6264634
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Grant note
- R01HL119476 / ; R01CA225027 / ; R01CA160433 / ; R01HL110907 / National Institutes of Health
- Language
- English
- Date published
- 12/03/2018
- Academic Unit
- Pathology; VPMA - Administration
- Record Identifier
- 9984186387002771
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