{"id":603155,"date":"2023-01-31T07:48:53","date_gmt":"2023-01-31T13:48:53","guid":{"rendered":"https:\/\/news.sellorbuyhomefast.com\/index.php\/2023\/01\/31\/the-case-of-the-incredibly-long-lived-mouse-cells\/"},"modified":"2023-01-31T07:48:53","modified_gmt":"2023-01-31T13:48:53","slug":"the-case-of-the-incredibly-long-lived-mouse-cells","status":"publish","type":"post","link":"https:\/\/newsycanuse.com\/index.php\/2023\/01\/31\/the-case-of-the-incredibly-long-lived-mouse-cells\/","title":{"rendered":"The Case of the Incredibly Long-Lived Mouse Cells"},"content":{"rendered":"
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David Masopust has<\/span> long imagined how to push immune systems to their limits\u2014how to rally the most powerful army of protective cells. But one of the big mysteries of immunology is that so far, nobody knows what those limits are. So he hatched a project: to keep mouse immune cells battle-ready as long as possible. \u201cThe idea was, let\u2019s keep doing this until the wheels fall off the bus,\u201d says Masopust, a professor of immunology at the University of Minnesota.<\/p>\n

But the wheels never fell off. He was able to keep those mouse cells alive longer than anyone thought possible\u2014indeed, much longer than the mice themselves.<\/p>\n

When your body first detects foreign bacteria, cancer, a virus, or vaccine, the\u00a0immune system\u2019s T cells log the presence of that invader, kill the cells it\u2019s infected, and form new T cells that carry the memory of how to fight it. Should the same intruder return later on, that protective T-cell army will swell to meet it.\u00a0<\/p>\n

But researchers have noticed that if you stimulate these T cells too many times, they\u2019ll get exhausted\u2014they\u2019ll become less responsive to threats and eventually die. \u201cIt was a concern,\u201d says Masopust. \u201cRaising\u00a0too large<\/em> of an army would turn the army into a bunch of zombie soldiers.\u201d Immunologists have considered this a fundamental limit on T cells\u2019 capacity to fight threats. Masopust, however, wasn\u2019t sold. \u201cWe wanted to test this principle.\u201d<\/p>\n

His team\u2019s experiment began by dosing mice with a viral vaccine that stirs up T cells. About two months later, they gave them another shot to rally the cells again for stronger immune memory. Then a third boost two months later. At this point, the immunized mouse T cells were absolutely\u00a0amped<\/em>. \u201cThey were too good at destroying whatever I gave them,\u201d Masopust says. \u201cThe viruses get snuffed out\u00a0too<\/em> quickly.\u201d\u00a0<\/p>\n

This didn\u2019t satisfy Masopust, so his team took cells from the immunized mice\u2019s spleens and lymph nodes, expanded the cell populations in test tubes, injected about 100,000 into new mice, and began immunizing them the same way. Once again, the mice got three shots over about 6 months. And once again, the T-cells kept fighting.<\/p>\n

So the scientists repeated the process again, taking the cells from this second generation of mice and injecting them into a third. And a fourth. And ultimately a\u00a0seventeenth<\/em>. They had created a kind of relay, in which the immune cells passed from one generation of mice to another eventually outlived the original mice. (They also outlasted the gigs of the first two researchers assigned to the project.) In results published on January 18 in\u00a0Nature<\/em>, Masopust\u2019s team reports keeping this T-cell army alive and active\u00a0for 10 years<\/a>\u2014longer than four mouse lifespans. It\u2019s the first evidence of such extreme longevity.<\/p>\n

\u201cT cells are born to be sprinters, but can be trained to become marathon runners\u201d thanks to repeated exposure to a challenge\u2014like a virus\u2014followed by rest periods, Masopust says.\u00a0The genetic changes exhibited by these cells after 10 years of this \u201ctraining\u201d may well describe what an extraordinarily fit T cell looks like.\u00a0Masopust thinks that researchers can\u00a0glean lessons from this experiment in order to treat cancer, create better vaccines, and understand or even slow human aging:\u00a0\u201cIt\u2019s spun off into so many different interesting questions that transcend immunology.\u201d<\/p>\n<\/div>\n

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\u201cIt\u2019s probably one of the most extraordinary papers in immunology that I\u2019ve seen, easily in the past decade,\u201d says John Wherry, director of the Institute of Immunology at the University of Pennsylvania\u2019s Perelman School of Medicine, who was not involved in the study. \u201cIt tells us that immunity can be\u00a0incredibly<\/em>\u00a0durable, if we understand how to generate it properly.\u201d\u00a0<\/p>\n

Andrew Soerens, a<\/span> postdoctoral immunologist who inherited the project 21 immunizations in, didn\u2019t expect it to become his main responsibility. \u201cIt felt like it could be the worst project ever, because it had no endpoint in mind. Or, it could be pretty cool because it was interesting biology,\u201d he recalls.\u00a0<\/p>\n

This project is not something a researcher would ever write a grant proposal for. It\u2019s an exploration that threatens to reverse an entrenched idea\u2014that T cells have an intrinsically limited capacity to fight\u2014with no guarantee of success. \u201cIt\u2019s almost a historically monumental experiment to do. No one does an experiment that lasts 10 years,\u201d says Wherry. \u201cIt\u2019s antithetical to funding mechanisms, and a five-year funding cycle\u2014which really means every three years you have to be doing something new. It\u2019s antithetical to the way we train our students and postdocs who typically are in a lab for four or five years. It\u2019s antithetical to the short attention span of scientists and the scientific environment we live in. So it really says something fundamental about really, really wanting to address a critically important question.\u201d<\/p>\n

Indeed, the project remained unfunded for the first eight years, surviving just on lab members\u2019 spare time. But its central question was ambitious: Must immune cells age? In 1961, microbiologist Leonard Hayflick\u00a0argued<\/a> that all of our cells (except eggs, sperm, and cancer) could only divide a finite number of times. In the 1980s, researchers\u00a0advanced the idea<\/a> that this might play out through the erosion of protective telomeres\u2014a sort of aglet at the end of chromosomes\u2014which shorten when cells divide. After enough divisions, there\u2019s no more telomere left to protect the genes.\u00a0<\/p>\n

This project challenged the Hayflick limit, and it soon commanded most of Soerens\u2019 time: He\u2019d run down to the mouse colony to immunize, take samples, and start new cohorts of T-cell armies.\u00a0He\u2019d count cells and parse the blend of proteins they produced, noting what had changed over the years. Such differences can indicate changes in a cell\u2019s genetic expression\u2014or even mutations in the gene sequence.<\/p>\n

One day, a change stood out: high levels of protein associated with cell death, called PD1. It\u2019s usually a sign of cell exhaustion. But these cells were not exhausted. They continued to\u00a0proliferate, combat microbial infections, and form long-lived memory cells, all functions the lab considered markers of fitness and longevity. \u201cI was kind of shocked,\u201d Soerens says. \u201cThat was probably the first time that I was actually very confident that this was\u00a0something<\/em>.\u201d\u00a0<\/p>\n

So the lab kept going, and going. Finally, says\u00a0Masopust,\u00a0\u201cthe question was, how long is long enough to keep this going before you\u2019ve made your point?\u201d Ten years, or four lifetimes, felt right. \u201cAn extreme of nature demonstration was where it was good enough for me.\u201d\u00a0(For the record: All those cell cohorts are still going.)<\/p>\n<\/div>\n

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Susan Kaech, a professor and director of immunobiology at the Salk Institute for Biological Studies, points out that long-lived immune memory isn\u2019t groundbreaking itself\u2014human T cells can survive\u00a0for decades if they remain unassailed. What\u2019s really unprecedented is that these have been subjected to a 10-year beatdown: \u201cIt\u2019d be like running a marathon every month,\u201d says Kaech, \u201cand you never got winded and your time never got longer.\u201d<\/p>\n

To Kaech, who was not involved in the study, the results hint that we\u2019d benefit from tailoring vaccination programs to T cells, and beefing up the immune response by repeatedly challenging those cells, as Masopust\u2019s triple-immunization strategy did for the mice. And immunologists have seen\u2014with SARS-CoV-2<\/a>\u00a0for<\/a>\u00a0example<\/a>\u2014that T cells bring the longest-lasting immunity. \u201cAs we saw the [SARS-CoV-2] virus mutate away from our antibody responses,\u201d she says, \u201cpeople were still protected\u2014in part because they had a wide array of memory T cells that recognized other parts of the virus.\u201d<\/p>\n

The new study may also provide insights for treating cancer. Tumors hammer T cells nonstop, and eventually wear them down. \u201cWe see this exhaustion and this functional impairment kick in. We don\u2019t really know exactly why,\u201d says Jeff Rathmell, an immunologist at Vanderbilt University who was not involved in the work. \u201cThe whole goal of cancer immunotherapy is to overcome that. And this just shows you that it\u2019s not like the cells have any intrinsic limit. They can continue to\u00a0go and go and go<\/em>.\u201d<\/p>\n

Rathmell thinks the insights from this paper might help advance a new approach called\u00a0CAR-T therapy<\/a>, in which doctors take a patient\u2019s T cells and genetically modify them\u00a0to better attack their tumor<\/a>. Masopust\u2019s team doesn\u2019t yet know what genetic changes explain the mouse cells\u2019 extraordinary fitness, but he and Rathmell think that mimicking those changes could make CAR-T more powerful.\u00a0<\/p>\n

Alternatively, if the long-lived cells produce more of a certain protein that could support immune cell function in patients with cancer, chronic viral infections, or autoimmune diseases, that could be useful information for drug developers.<\/p>\n

He and Wherry hope that Masopust\u2019s mice can be a model for healthier aging. As people get older, their immune health declines as some T cells stay healthy, but others die or tire out. Pinpointing which genetic changes explain why some cells can achieve extreme longevity may offer clues about how to extend human immune health. \u201cIf T cells\u00a0can<\/em> stay alive forever,\u201d Wherry wonders, \u201chow do we actually keep the good T cells around?\u201d<\/p>\n

There are other big questions to answer, too, like why these mouse cells were able to proliferate without becoming cancerous\u2014do they have some outrageous knack for repairing themselves to prevent mutation? Why does rest between viral challenges seem to be so important, and how long does that rest have to last? And was Hayflick perhaps too pessimistic? \u201cThe Hayflick limit has been around forever. But this data would say that it\u2019s incomplete, or maybe even just wrong,\u201d says Rathmell. \u201cI mean, talk about a finding that changes dogma.\u201d<\/p>\n<\/div>\n<\/div>\n

Read More<\/a>
\n Max G. Levy<\/p>\n","protected":false},"excerpt":{"rendered":"

David Masopust has long imagined how to push immune systems to their limits\u2014how to rally the most powerful army of protective cells. But one of the big mysteries of immunology is that so far, nobody knows what those limits are. So he hatched a project: to keep mouse immune cells battle-ready as long as possible.<\/p>\n","protected":false},"author":1,"featured_media":603156,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[1745,118642,46],"tags":[],"class_list":{"0":"post-603155","1":"post","2":"type-post","3":"status-publish","4":"format-standard","5":"has-post-thumbnail","7":"category-incredibly","8":"category-long-lived","9":"category-technology"},"aioseo_notices":[],"_links":{"self":[{"href":"https:\/\/newsycanuse.com\/index.php\/wp-json\/wp\/v2\/posts\/603155","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/newsycanuse.com\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/newsycanuse.com\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/newsycanuse.com\/index.php\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/newsycanuse.com\/index.php\/wp-json\/wp\/v2\/comments?post=603155"}],"version-history":[{"count":0,"href":"https:\/\/newsycanuse.com\/index.php\/wp-json\/wp\/v2\/posts\/603155\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/newsycanuse.com\/index.php\/wp-json\/wp\/v2\/media\/603156"}],"wp:attachment":[{"href":"https:\/\/newsycanuse.com\/index.php\/wp-json\/wp\/v2\/media?parent=603155"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/newsycanuse.com\/index.php\/wp-json\/wp\/v2\/categories?post=603155"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/newsycanuse.com\/index.php\/wp-json\/wp\/v2\/tags?post=603155"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}