Telomeres contain genetic information of chromosome. The telomeres of all cells wear and shrink with age, which limits cell division and proliferation. Researchers at Johns Hopkins University found people’s immune systems cells age and die prematurely, who are born with abnormally short telomeres (ST).
The mechanisms that drive T cell aging are not understood. The research shows 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.
The researchers examined the transcriptional programs of T cells from telomerase mutation carriers; finding that 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.
The mouse study showed telomerase-null mice with short TL showed defects throughout T cell development, including increased apoptosis of stimulated thymocyte, their intrathymic precursors, in addition to depleted hematopoietic reserves.
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. The data suggest there are TL-dependent and TL-independent mechanisms that differentially contribute to distinct molecular programs of T cell apoptosis with aging.