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.

Long telomeres and cancer risk: the price of cellular immortality

“…The high frequency of telomere defects in IPF and the prevalence of this disease make IPF the most common of the human short telomere phenotypes. A subset of adult IPF patients show extrapulmonary short telomere syndrome features including bone marrow failure, immunodeficiency, and liver disease; their recognition is critical for the diagnosis and management of these patients (18,21,(41)(42)(43)47).…”

“…As we will discuss here, disorders of telomere length are increasingly appreciated as causing clinically recognizable disease processes (13). The short telomere syndromes are now phenotypically and genetically well characterized (14)(15)(16)(17)(18)(19). This knowledge is increasingly integrated into clinical algorithms, especially for patients with lung disease and bone marrow failure (20,21).…”

Identification of rare HIV-1–infected patients with extreme CD4+ T cell decline despite ART-mediated viral suppression

“…EXID2 was found to have a remarkable inflammasome/caspase-1 activation along with severe decrease in TL, with an RTEL1 frameshift variant introducing an early stop codon. Such a clinical scenario may resemble the recently reported novel quantitative and qualitative primary T cell immunodeficiency in which telomere shortening caused by specific genetic defects reaches a critical cellular threshold causing depletion of CD4 + T cells from intrinsic and extrinsic apoptosis (29). It is conceivable that, as seen in this model, in EXID2, the telomere attrition caused by T cell replication in a perinatal HIV-1 infection with persistent vigorous inflammasome/caspase-1 activation could not be fully compensated for in the context of the frameshift variant in RTEL1 and reached a critical threshold in naive and memory T cells (7,29,30).…”

Idiopathic pulmonary fibrosis lung transplant recipients are at increased risk for EBV-associated posttransplant lymphoproliferative disorder and worse survival

“…One possible explanation for these findings is an impaired ability of IPF patients on IST to control EBV chronic infection. We previously demonstrated an increased susceptibility to CMV, another herpesvirus infection in patients with IPF and short telomeres in association with impaired viral immunity posttransplant, possibly related to changes in T cell immunity . In this historical cohort, blood samples were not available for all patients to assess telomere length in those who developed PTLD.…”