Short telomere syndromes cause a primary T cell immunodeficiency

Christa L. Wagner, Vidya Sagar Hanumanthu, C. Conover Talbot, Roshini S. Abraham, David Hamm, Dustin L. Gable, Christopher G. Kanakry, Carolyn D. Applegate, Janet M Siliciano, J. Brooks Jackson, Stephen Desiderio, Jonathan Alder, Leo Luznik, Mary Armanios

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)5222-5234
Number of pages13
JournalJournal of Clinical Investigation
Volume128
Issue number12
DOIs
StatePublished - Dec 3 2018

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Wagner, C. L., Hanumanthu, V. S., Conover Talbot, C., Abraham, R. S., Hamm, D., Gable, D. L., Kanakry, C. G., Applegate, C. D., Siliciano, J. M., Brooks Jackson, J., Desiderio, S., Alder, J., Luznik, L., & Armanios, M. (2018). Short telomere syndromes cause a primary T cell immunodeficiency. Journal of Clinical Investigation, 128(12), 5222-5234. https://doi.org/10.1172/JCI120216