T cells replicate aggressively in response to infection and other threats, yet these cells must also persist in the body for years in order to maintain immunological memory. Telomeres, repeated DNA sequences at the ends of chromosomes, shorten with each cell division. This mechanism forms a part of the Hayflick limit on somatic cell replication. When telomeres become too short, cells become senescent and self-destruct, or are destroyed by immune cells. T cells can employ telomerase to lengthen telomeres, but not to any great degree. So how do they manage such long lives in an environment of repeated threats by pathogens, and thus repeated bursts of telomere-shortening replication?
In today's open access paper, the authors outline a fascinating mechanism by which antigen-presenting B cells, which interact with T cells to coordinate the immune response, donate telomeres to those T cells, thereby increasing their replicative life span. One initial thought in response to this finding is that it should be possible to create telomere-bearing vesicles to replicate this effect, more broadly than it occurs naturally. As is the case for telomerase gene therapy, and all such analogous approaches aimed at lengthening telomeres, there is the issue of selectivity, however. Extending telomeres in cells that probably should be destroyed as well as those that will continue beneficial work is a concern, even given the very positive data in mice resulting from upregulation of telomerase.
The common view is that T lymphocytes activate telomerase to delay senescence. Here we show that some T cells (primarily naïve and central memory< cells) elongated telomeres by acquiring telomere vesicles from antigen-presenting cells (APCs) independently of telomerase action. Upon contact with these T cells, APCs degraded shelterin to donate telomeres, which were cleaved by the telomere trimming factor TZAP, and then transferred in extracellular vesicles at the immunological synapse.
Telomere vesicles retained the Rad51 recombination factor that enabled telomere fusion with T-cell chromosome ends lengthening them by an average of ~3,000 base pairs. Thus, there are antigen-specific populations of T cells whose ageing fate decisions are based on telomere vesicle transfer upon initial contact with APCs. These telomere-acquiring T cells are protected from senescence before clonal division begins, conferring long-lasting immune protection.
How senescent T cells are formed remains poorly understood. We propose a model whereby telomere transfer from APCs protects the recipient T cells from replicative senescence. The recipient is preferably a naïve or central memory T cell. When recipient T cells acquire telomeres from APCs during antigen presentation, they shift towards a stem-like/central long-lived memory state. Failure to acquire telomeres skews them towards senescence instead.
It is not clear how T cells with APC telomeres will divide upon telomere transfer; however, these T cells may subsequently divide and differentiate both linearly and/or asymmetrically after antigen stimulation, if telomere transfer occurs. It is possible that antigen strength may affect the amount of telomere transfer and subsequent division of T cells. However, even in situations where antigen specificity was identical, a large proportion of T cells still failed to acquire telomeres from APCs, shifting towards a short-lived effector state; some of these cells may serve as senescent progenitors. Therefore, additional mechanisms controlling telomere transfer during antigen presentation beyond T-cell receptor specificity would have to exist.
We suggest that senescent T cells, or their progenitors, may be short-lived cells that are continuously generated by episodes of activation that lack telomere transfer. An important but as-yet-undefined function of the immunological synapse is, therefore, immediate determination of senescence fates of T cells. The intercellular telomere transfer reaction described is a different form of decentralized immunity whereby APCs distribute telomeres to favour some T cells becoming long-lived memory cells, bypassing senescence. Decentralization indicates that T cells do not rely on just a single molecule, telomerase, to extend telomeres. Whether the memory T cells generated in the absence of telomere transfer have the same longevity outlook than those telomere-acquiring T cells we have studied remains to be determined.
View the full article at FightAging
