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 3

T cell–intrinsic apoptosis contributes to T cell lymphopenia.

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T cell–intrinsic apoptosis contributes to T cell lymphopenia. (A) Schema...
(A) Schematic for congenic transplant of bone marrow hematopoietic stem progenitor cells (HSPCs), defined as lineage-negative population. Cells were transplanted into WT or fourth-generation telomerase RNA-null mice (mTR–/–G4). Donor-derived T cell fractions were assessed. (B and C) Quantification of donor-derived CD4+ and CD8+ T cells in thymuses and peripheral blood at 4 and 8 weeks after transplantation for WT and mTR–/–G4 recipient mice (n = 6 recipients were studied, 3 male/3 female for each genotype at each time point). (D) Thymocyte apoptosis rates in CD3negCD4–CD8– (DN) populations 1, 2, 3, and 4, defined by their cell-surface markers, as shown. (E) Apoptotic fraction of CD3loCD4+CD8+ (DP) thymocytes in newborn. (F and G) Apoptotic fraction of CD3hiCD4+ and CD3hiCD8+ thymocytes. For D–G, the apoptotic fraction was quantified as the total annexin V+ population in newborn mice (1 week old, n = 6/group, sex not determined because of young age). (H–J) Peripheral blood absolute CD4+, CD8+ T cell counts and the CD4/CD8 ratio, respectively. For H–J, n = 10 WT, 7 male/3 female, n = 9 mTR–/–G4, 4 male/5 female, 6–16 weeks). (K) Peripheral T cell apoptosis quantified at 48 hours as total annexin V+ PIneg plus annexin V+ PIlo populations for splenocytes stimulated with CD3/CD28. Total T cells were isolated from 10 WT (7 female/3 male) and 9 mTR–/–G4 (4 female/3 male), 20–25 weeks; 7 old WT (5 female/2 male), 55–67 weeks. (L) Apoptosis quantified at 48 hours (as in K) for T cells isolated from peripheral blood of YC (n = 13, 8 male/5 female), ST (n = 9, 3 male/6 female), and OA (n = 5, 3 male/2 female). The analysis for K and L included total T cells. Error bars represent SEM. *P < 0.05; **P < 0.01, Mann-Whitney U test.