LLike all cells in our body, immune cells age. Over time, they become less and less able to fight infections, cancer, and disease. Previously, researchers believed that the process of aging and weakening of cells, known as cellular senescence, was an inevitable consequence of routine infection and time. But a study published yesterday (September 15) in Cell Biology Nature suggests that an interaction between T cells and antigen-presenting cells (APCs) early in the immune response to viruses may determine the rate at which T cells decline.
Telomeres are long, repeated sequences of DNA that squeeze chromosomes together and protect their ends from unraveling. As cells age, their telomeres get shorter and shorter with each cell division until they can no longer divide. The new study finds that after infection, APCs, the cells that initially trigger the T cell immune response by presenting them with a foreign antigen, cut and deliver their telomeres to T cells, the virus-fighting white blood cells.
The 46 human chromosomes are shown in blue, with telomeres appearing as white dots.
Credit: Hesed Padilla-Nash and Thomas Ried, National Cancer Institute, National Institutes of Health
The researchers found that when APCS deliver their telomeres to T cells, the latter transform into a stem cell-like configuration, which delays their senescence. The researchers also found that this interaction boosts long-term immunity in mice, suggesting that this finding could pave the way for more effective vaccination.
“This article is really fascinating,” says Anthony J. Corravubias, an immunologist at UCLA who was not involved in the study. He says the paper[s] light on a really interesting mechanism that prevents T cells from becoming senescent.
Extension of cell life via telomeres
When a foreign invader such as a virus enters the body, the T cells rapidly divide and their numbers skyrocket. Previously, scientists knew that T cells employed telomerase, an enzyme that stretches telomeres, to combat telomere loss during this rapid division, which over time can lead to shortened telomeres and eventual senescence. But telomerase is not enough to prevent T cell senescence, prompting scientists to search for another key mechanism responsible for protecting T cells from aging.
The researchers, a team from the University of College London led by immunologist Alessio Lanna, first looked at the role telomeres play in aging immune cells and analyzed telomere length during the immune response. when they discovered telomere donation. (Lanna is also CEO of Sentcell, a biotech company that aims to increase human lifespan by rejuvenating T cells.)
To isolate the immune cells, Lanna and his collaborators derived T cells and APC cells from the blood of human research participants and then cultured those cells. Then they exposed the cells to a mixture of antigens made up of pieces of various viruses, to ensure that the APC and T cells come together to replicate a true immune response. Finally, they analyzed the length of the cells’ respective telomeres with a sequencing technique.
See “Can destroying senescent cells treat age-related diseases?”
“We were looking at immune synapses between T cells and antigen-presenting cells when we made an unexpected observation,” says Lanna. When the APC and T cells they observed joined, the T cell telomeres lengthened, while the APC telomeres shrank. This action extended the telomeres of the receptor T cells up to 30 times more than telomerase would.
To determine whether the APCs were indeed donating their telomeres, the researchers labeled the APC telomeres with fluorescent markers. After the cells were presented with an antigen, the team of scientists saw clusters of telomeres leaving the APC nuclei and congregating at the junctions between the APC cells and the T cells. The researchers then isolated these telomere-filled vesicles using fluorescence-activated vesicle sorting. Once the APC-derived vesicles were delivered to T cells, even in the absence of APC, the T cells took up the APC telomeric DNA and stuck it to the ends of their chromosomes.
These vesicles increased T cell proliferation and decreased T cell count with senescence marker proteins, and protected T cell populations with short telomeres from early aging, the team found. There was also an increase in the number of stem-like memory T cells, which are able to perform effector or memory functions if they encounter a pathogen again. Effector cells are involved in increasing inflammation and killing infected cells, while memory cells retain information about threats to the body to trigger future immune responses.
Previous studies by other groups had determined that in the more stem cell-like configuration, T cells live longer than those that have differentiated, Lanna says. The results suggest that the fate of some T cells, whether they become senescent or not, is determined when APCs deliver telomeres to T cells. This means that the fate of some T cells is sealed before the immune response even begins. . “It’s against dogma in the area of immune senescence,” Lanna says.
In vivo immunity enhancement
This telomere donation also appears to boost long-term immunity in mice. In another experiment, the researchers exposed T cells to a flu vaccine, then exposed one group of T cells to vesicles filled with APC-derived telomeres, and another group to vesicles without telomeres. They then injected T cells into separate groups of mice that were also exposed to H1N1, a strain of flu commonly known as swine flu. Mice that received neither type of treatment died almost instantly from the flu, but both types of T-cell treatment seemed to protect the mice after the virus was injected. After 15 days, the researchers again exposed the two groups of mice to H1N1. The mice that received the T cells exposed to telomere-filled vesicles still had a robust immune response to the H1N1 injection, but the other group treated with the T cells died immediately. This suggests that APC-derived vesicles could help T cells maintain their immune function over time, the researchers say.
“We know that we can administer these vesicles to an animal and that will protect the animal in the long term against infection,” says Lanna. The vesicles could even be incorporated into vaccines to prolong the effectiveness of vaccination, he suggests, or eliminate the need for boosters.
The researchers also observed that APCs deliver telomeres to some T cells and not others, although the reason is unclear. Using Flow-FISH, a test that counts cells and analyzes their telomere length one by one, the team found that naïve T cells – cells that have never encountered an antigen – and T cells memory were more likely to absorb telomeres. Meanwhile, various types of effector T cells are less likely to do so.
In addition to their potential application to vaccines, these findings may open up the possibility of treatments that stimulate the release of APC vesicles and make T cells more likely to accept the vesicles, or technologies that extract and deliver vesicles, Lanna says. T-cell senescence has been linked to an increased risk of infections, cancers and dementia, he adds, and such treatments could potentially help delay immune aging and related diseases.
“I think this is a really great study that has a lot of clinical potential, in terms of vaccine efficacy,” Corravubias says. Additionally, “it would be interesting if you could treat patients who are either chronically infected or preventatively to help build their immunity against different infections.”