Nature sub-issue: A new mechanism to fight immune aging! Scientists have found that antigen-presenting cells actively present telomeres to T cells, helping T cells prolong their life

*For medical professionals only

The aging of cells can cause different degrees of organ dysfunction, inflammation and decreased immunity, making the body susceptible to aging-related diseases such as infections and tumors
.

Telomeres are TTAGGG repeats located at the ends of chromosomes that protect the ends of chromosomes and prolong cell life cycles [1].

Telomeres are like the "life bar" of cells, which shorten with each cell division, which is the main reason why
cells enter aging.
When the "life progress bar" is too short (telomere length< 4kb), it announces that the cell has entered aging and eventually apoptosis [2].
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In order to avoid the shortening of telomeres, cells also have their own "survival mechanism", mainly including telomerase-dependent and non-telomerase dependent two pathways [3].

We know that in the immune system, the production of memory T cells is an important link in the body's anti-tumor and anti-pathogen invasion, and its lifespan is closely related
to the health of the human body.
But little is known about how memory T cells maintain their lifespan
.

Recently, a research team led by Professor Alessio Lanna of University College London published interesting research results on the mechanism of memory T cell life extension in the top international journal Nature Cell Biology [4].

They found that during antigen presentation, antigen-presenting cells (APCs) actively "donate" their telomeres to T cells through vesicles to help T cells extend their lifespan [4].

Their research discovered the phenomenon of telomere transfer between cells for the first time, revealed a pathway to lengthen telomeres in a "passive" way, opened a new chapter in the field of cellular aging and anti-aging, and provided new research ideas
for the treatment of aging-related diseases.

Immune synapses are special structures formed by MHC molecular-antigen complexes and T cell receptors (TCRs) when APCs present antigens to T cells [5].

Studies have shown that the stimulation of immune synapses activates T cells and expands them, but also activates the T cells' own telomerase, allowing them to actively prolong the "life progress bar" [6].

However, this is not enough for T cells to successfully resist aging and form long-term immunity in large-scale clonal expansion [7].

And studies have proved that repeated antigen stimulation can rapidly reduce the activity of T cell telomerase [8].

This begs the question: Do memory T cells have other secrets to longevity?

The answer lies in
APC's interaction with T cells.

First, in vitro, the researchers found through telomere restriction fragment (TEF) analysis that after the formation of immune synapses, the telomeres of T cells were lengthened, while the telomeres of APCs were correspondingly shortened
.

TEF results showed that after the formation of immune synapses, T cell telomeres lengthened, while APC telomeres were shortened

Using labeling and fluorescence tracing techniques, they demonstrated that when immune synapses form, telomeres of APCs are transferred through vesicles into T cells and integrated into the chromosomes of T cells
.

They also showed that the phenomenon is not dependent on telomerase
in T cells.
In addition, ionomycin, which initiates calcium influx signals, can also cause APC to release telomere vesicles
.

After confirming the phenomenon, the researchers designed a model of artificial immune synaptic bilayer to further explore the mechanism
of telomere vesicle release and recombination in vitro.

First, through immunoblotting and ELISA, they found that telomere-containing vesicles had telomere-zinc-finger-related protein (TZAP), while telomere-free vesicles did not
.

The function of TZAP is to prune long telomeres [9].

They found that antigen stimulation or calcium influx could lead to increased
expression of TZAP protein in APCs.
After knocking down TZAP, the telomere vesicles secreted by APC are reduced, thus demonstrating that the cleavage of telomeres by TZAP plays an important role
in the passage of telomeres into the vesicles.

Previous studies have demonstrated that the telomel complex (shelterin) binds to telomeres to prevent telomeres from being sheared by the TZAP protein [9].

Researchers have shown that stimulation of immune synapses or calcium ion influx can trigger the degradation of telomere protein complexes (such as POT1 and TRF2) in APCs through the proteasome pathway, allowing TZAP to "take advantage of the void" and lead to telomere cleavage
.

Next, the researchers explored inside CD4⁺ T cells how telomeres given by APCs were attached to the T cells
' own genomes.
They hypothesized that the homologous recombinant factor Rad51 [10], which is involved in telomere lengthening, may play a major role
in this.

First, they verified that Rad51 is present in
most vesicles containing telomeres.

Further, by knocking down Rad51 in APC cells, they found that APC's ability to secrete telomere vesicles was not significantly altered, but the ability of APC telomere DNA to integrate into the T cell genome was significantly limited
.
They concluded that Rad51 plays a major role
in the integration of metastatic telomeres into the T cell genome.

Finally, the researchers verified the phenomenon
of telomere transfer of APC-T cells in vivo through the OT-II mouse model.

Further, the researchers found through in vivo tracking of CD45.
1/2 T cells that in CD45.
1 mice, T cells that obtained telomeres (Tel⁺T) expanded more significantly under the stimulation of OVA antigen than T cells without telomeres (^Tel-T).
Telomere transfer thus proves that stronger T cell immune responses
.

On the other hand, in order to test the ability of immune memory formation, they stimulated recipient mice again with OVA after 40 days of intravenous T cells, and then tested the composition of recipient lymph nodes and spleen intra-T cells after 15 days, and the results proved that Tel⁺ T cells not only expanded more, but also formed more memory T cells
.

Tel⁺ T cells form more memory T cells

The researchers co-cultured CD45.
2 OT-II CD4⁺ T cells with knock-down (siRad15) and non-knocked Rad15 (siCtrl) APC telomere vesicles, and then used similar in vivo experimental methods to verify the important role
of Rad51 in telomere transfer and long-term immune memory maintenance.

In order to demonstrate the short- and long-term effects of telomere transfer on immune defense, the researchers used adoptive immune cell therapy to extract FLUAD virus-specific T cells from donor mice and co-culture them with telomere-containing and telomere-free vesicles, and then adopted into recipient mice to be stimulated
with the virus after 18 hours or 15 days.

The results showed that in the immune effector stage (after 18 hours), whether T cells obtained APC telomeres did not make a significant difference in the survival rate of mice, but in the immune memory stage (after 15 days), Tel⁺ T cells could make the survival rate of mice significantly higher than that of ^Tel-T cells.
It is thus proved that telomere transfer plays an important role
in the formation of long-term immune memory.

In the immune memory stage, Tel⁺T significantly prolongs the survival of mice

In summary, Professor Alessio Lanna's research team found that APCs "selflessly" their telomeres to T cells, thereby helping T cells "survive", enhance immune responses and stabilize long-term immune memory
.

Their work shows the direct link between cellular aging, telomere shortening, and age-related immunity, demystifying APC and uncovering its untold side – the "altruistic" cells that sacrifice their lifespan to survive T cells
.

This imaginative study inevitably arouses people's reverie, is there a similar phenomenon on other cells? Can telomere vesicles be used in anti-aging treatments? Let's look forward to the future exploration
of scientists.

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Responsible editorYing Yuyan