Short telomere syndromes cause a primary T cell immunodeficiency
Christa L. Wagner, … , Leo Luznik, Mary Armanios
Christa L. Wagner, … , Leo Luznik, Mary Armanios
Published September 4, 2018
Citation Information: J Clin Invest. 2018;128(12):5222-5234. https://doi.org/10.1172/JCI120216.
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Research Article Aging Genetics Article has an altmetric score of 344

Short telomere syndromes cause a primary T cell immunodeficiency

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.

Authors

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

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Figure 4

The TCR repertoire is restricted in telomerase mutation carriers.

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The TCR repertoire is restricted in telomerase mutation carriers. (A) Ex...
(A) Expression of 24 Vβ proteins by flow cytometry for YC, ST, and OA relative to 85 controls. Each column represents data from a single individual, with gray representing percentage of Vβ-expressing T cells within 1 SD from the mean and the colors representing greater deviation from means derived from controls. The degree of deviation is noted in the key. Data are shown for CD3+, CD4+, and CD8+ T cells and are summarized in the bottom 2 rows. (B–D) Bar graphs show mean number of Vβ families deviating 1–2, or more than 2, SD for CD3+, CD4+, and CD8+ T cells, respectively. n = 6 YC, 2 male/4 female; n = 7 ST, 2 male/5 female; n = 5 OA, 3 male/2 female. Error bars in B–D represent SEM. (E) T cell diversity as measured by the mean unique sequences per T cell determined by deep sequencing of the CDR3 of the TCR-β gene on sorted CD8+ T cells (n = 4/group, 2 male/2 female for each). (F) Unique productive sequences per CD8+ T cell for data generated for E. Whiskers in E and F mark the minimum and maximum values. (G) Pielou’s J index, a calculation of evenness of Vβ usage where 1 represents an even distribution and 0 represents complete dominance of 1 Vβ. (H) Dot plot of total usage of the 20 most frequently utilized Vβ genes in YC compared with ST subjects shows a higher usage in ST patients. Inset shows summed usage frequency of the top 5 most frequently used Vβ genes; the increased usage of highly utilized genes is reflected in a decreased usage of the subsequent Vβ genes (i.e., those ranked 6 to 20). *P < 0.05; **P < 0.01, Mann-Whitney U test.