TY - JOUR
T1 - Short telomere syndromes cause a primary T cell immunodeficiency
AU - Wagner, Christa L.
AU - Hanumanthu, Vidya Sagar
AU - Conover Talbot, C.
AU - Abraham, Roshini S.
AU - Hamm, David
AU - Gable, Dustin L.
AU - Kanakry, Christopher G.
AU - Applegate, Carolyn D.
AU - Siliciano, Janet
AU - Brooks Jackson, J.
AU - Desiderio, Stephen
AU - Alder, Jonathan
AU - Luznik, Leo
AU - Armanios, Mary
N1 - Publisher Copyright:
Copyright 2018, American Society for Clinical Investigation.
PY - 2018/12/3
Y1 - 2018/12/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85058320262&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85058320262&partnerID=8YFLogxK
U2 - 10.1172/JCI120216
DO - 10.1172/JCI120216
M3 - Article
C2 - 30179220
AN - SCOPUS:85058320262
SN - 0021-9738
VL - 128
SP - 5222
EP - 5234
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 12
ER -