Short telomere syndromes cause a primary T cell immunodeficiency
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
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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Research Article Aging Genetics

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 5

Distinct pathways to apoptosis in short telomere and OA T cells.

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Distinct pathways to apoptosis in short telomere and OA T cells. (A) Hea...
(A) Heatmap and dendrogram of gene expression showing the mean subtracted expression values on a log2 scale. For each of 12 samples, YC, ST, and OA groups (2 male/2 female/group), the log2 expression value was subtracted from the mean log2 expression value of the entire cohort. The dendrogram showing relatedness of the samples is above, and relatedness of the gene transcripts is to the left. The differential change in gene expression is shown as positive and negative change on color scale indicated in key. (B) Venn diagram shows 4 of 20 nonoverlapping upregulated pathways in IPA involved in apoptosis. (C and D) CD95 expression in CD4+ and CD8+ T cells, respectively. (E and F) PD-1 expression in CD4+ and CD8+ T cells, respectively. For C–F, n = 5 YC, 2 male/3 female; n = 6 ST, 2 male/4 female; and n = 5 OA, 3 male/2 female. (G and H) Kap1 and p-Kap1 levels on protein from isolated mouse T splenocytes. p-Kap1 and actin were detected first. Then the blot was stripped and reblotted with Kap1 antibody. Protein from irradiated splenocytes is a positive control. (H) Shown are quantification data from 3 independent Western blots from a total of 11 mice: WT (30 weeks, 1 male/3 female), mTR–/–G4 (30–33 weeks, 4 female), and old WT mice (50–73 weeks, 3 female). (I) qRT-PCR from unstimulated T splenocytes. Each data point represents an independent experiment with ages similar to those in H. (J) Model of T cell–aging mechanisms showing differences in immunophenotype and T cell apoptosis program in young ST T cells and OA with normal TL. Older individuals with short telomeres are predicted to have extrinsic and intrinsic apoptotic mechanisms contributing. Error bars represent SEM. *P < 0.05; **P < 0.01, Student’s t test.