Abstract
BackgroundDeclining telomere length (TL) is associated with T cell senescence. While TL in naïve and memory T cells declines with increasing age, there is limited data on TL dynamics in virus-specific memory CD4+ T cells in healthy adults. We combined BrdU-labeling of virus-stimulated T cells followed with flow cytometry-fluorescent in situ hybridization for TL determination. We analyzed TL in T cells specific for several virus infections: non-recurring acute (vaccinia virus, VACV), recurring-acute (influenza A virus, IAV), and reactivating viruses (varicella-zoster virus, VZV, and cytomegalovirus, CMV) in 10 healthy subjects. Additionally, five subjects provided multiple blood samples separated by up to 10 years.ResultsVACV- and CMV-specific T cells had longer average TL than IAV-specific CD4+ T cells. Although most virus-specific cells were CD45RA-, we observed a minor population of BrdU+ CD45RA+ T cells characterized by long telomeres. Longitudinal analysis demonstrated a slow decline in average TL in virus-specific T cells. However, in one subject, VZV reactivation led to an increase in average TL in VZV-specific memory T cells, suggesting a conversion of longer TL cells from the naïve T cell repertoire.ConclusionsTLs in memory CD4+ T cells in otherwise healthy adults are heterogeneous and follow distinct virus-specific kinetics. These findings suggests that the distribution of TL and the creation and maintenance of long TL memory T cells could be important for the persistence of long-lived T cell memory.
Highlights
Declining telomere length (TL) is associated with T cell senescence
Since the frequency of virus-specific memory T cells in Peripheral blood mononuclear cell (PBMC) is generally too low in healthy humans for a robust TL analysis directly ex vivo, we expanded PBMC in vitro with viral antigens. To determine how this in vitro expansion may have affected TL, we compared TL in total T cells isolated from fresh PBMC to in vitro-expanded T cells using flowFISH [28]
Initial flowFISH experiments revealed inflated TL measurements in the in vitro expanded T cells (p
Summary
Declining telomere length (TL) is associated with T cell senescence. While TL in naïve and memory T cells declines with increasing age, there is limited data on TL dynamics in virus-specific memory CD4+ T cells in healthy adults. Periodic antigen-driven reactivation of memory T cells specific for recurrent or latent infections could drive additional rounds of proliferation with expression of telomerase to explain their continuing persistence [17,20], other data suggest that telomerase expression declines with each round of activation [19]. This explanation fails in the face of reports of detectable poxvirus-specific T cells 5 to 6 decades after a smallpox vaccination, a situation where there are no recurring exposures [2]. A substantially increased TL in this memory subset, relative to more differentiated memory T cells, could provide a mechanistic explanation for the in vivo longevity of the TSCM cells
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