Faculty Collaboration Database

Short telomere syndromes cause a primary T cell immunodeficiency. J Clin Invest 2018 Dec 03;128(12):5222-5234

Date

09/05/2018

Pubmed ID

30179220

Pubmed Central ID

PMC6264634

DOI

10.1172/JCI120216

Scopus ID

2-s2.0-85058320262 (requires institutional sign-in at Scopus site)   71 Citations

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.

Author List

Wagner CL, Hanumanthu VS, Talbot CC Jr, Abraham RS, Hamm D, Gable DL, Kanakry CG, Applegate CD, Siliciano J, Jackson JB, Desiderio S, Alder JK, Luznik L, Armanios M

Author

Christa Wagner PhD Director, Assistant Professor in the Institute for Health and Equity department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aging
Animals
Apoptosis
DNA Damage
Female
Growth Disorders
Humans
Hypercalcemia
Immunologic Deficiency Syndromes
Male
Metabolic Diseases
Mice
Mice, Knockout
Mutation
Nephrocalcinosis
T-Lymphocytes
Telomerase
Telomere Homeostasis