Antigen Presenting Cells Donate Telomeres to T Cells to Increase their Longevity

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.

An intercellular transfer of telomeres rescues T cells from senescence and promotes long-term immunological memory

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.


How can TELOMERES asking and not telomerase be transferred from cell to cell? Aren't they just a part of the gene, like the head in the zipper which gets worn down?

I will have to read again the news and the original article

Posted by: Cuberat at September 22nd, 2022 3:08 PM

Amazing what our cells are capable of. I wonder if we could ever figure out how these processes work and try to make them more universal across other cell types.

Posted by: Matt at September 22nd, 2022 4:33 PM

Another point confirmed once again with this finding is that blood tests measuring telomere length has no connection with life length. Yet this lack of connection don't translate in any way into lack of connection of telomere length of other tissues with life span. The main reason for creation of senescent cells is replicative senescence, caused by the very shortening of telomeres. So it was obvious for a long time that telomere length overall in the body HAS strong link with life length. The safest way to get rid of senescent cells is to prevent creation of them in the first place, by extending telomeres. On the up-to-date list of things to repair in the body, telomeres and telomerase is the most important.

BTW. It's very old news now, circulating on other sites for almost two years now, as it was published as a preprint in October 2020.

Posted by: SilverSeeker at September 23rd, 2022 7:54 AM

'While examining the the data associated with this paper I noticed an odd feature of the data in Figure 1G. The values for telomere vesicle size are given to 2 decimal points in nanometers. However, I observed that a number of values were repeated several times. Moreover, these repeated values were often clustered near each other in the unsorted list that was provided. It
seems strange that multiple vesicles would have precisely the same size to 2 decimal points.'

Posted by: Jones at September 29th, 2022 10:31 AM
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