Long-term memory T cells, which can remember an infection for decades before rousing themselves to action as needed, should the infection reoccur, are great sleepers. They are in some respects like ordinary memory cells, from which they are derived, but they enter a quiescent state, dividing less frequently than once every year and living more than 10 times longer than the average T cell. And while these slumbering T cells may superficially resemble ordinary T cells, innocent of infection, they harbor unique epigenetic marks. Acquired in battles against infection, these marks persist, ensuring that when the sleeper awakes, it responds rapidly to the return of old adversaries.

New details about the origin and longevity of human memory CD8+ T cells have emerged from a study led by researchers based at the University of California, Berkeley. These researchers, led by Mark Hellerstein, M.D., Ph.D., resolved a long-standing question about long-term memory T cells: Do they go through an effector stage—that is, do they transition through the naïve-to-effector and memory stages of T cell differentiation—or do they follow a separate pathway of their own?

When someone gets a vaccine or is exposed to a new infectious agent, cells that recognize the invader but had never have been called into action before—called naïve cells—respond by dividing prodigiously and developing infection-fighting functions. This creates a large pool of so-called memory cells, named for their ability to remember the specific infectious agent and respond effectively to repeat threats later. Over time, the large pool shrinks to a small number of long-term memory cells, which are primed to provide late protection. But scientists have debated how these memory cells are maintained and ready to strike for so long after the initial exposure.

Dr. Hellerstein and colleagues established that long-term memory T cells represent a subset of effector T cells, and they did so by using a method developed for HIV/AIDS research, but which has since come to be widely used to track the birth and death of human cells in the body.

The research team had subjects drink small amounts of water that had deuterium instead of hydrogen. Deuterium is nontoxic, but it is slightly heavier than hydrogen, so scientists can track it by mass spectrometry when it gets incorporated into newly replicated DNA in the body's cells, which occurs only during cell division.

Using this method, scientists can learn if a pool of cells is new or old, because newly born cells will have deuterium in their DNA. Scientists or clinicians monitoring the cells over time will see that the deuterium levels in short-lived cells will be diluted after the patients return to drinking regular water, while the deuterium levels in long-lived cells will remain high.

In the new study, people drank the deuterium water at different times after receiving the live yellow fever virus (YFV) vaccine, and researchers then isolated T cells from the patients and analyzed their deuterium content. Essentially, the scientists used in vivo deuterium labeling to mark CD8 T cells that proliferated in response to the virus and then assessed cellular turnover and longevity by quantifying deuterium dilution kinetics in virus-specific CD8 T cells

The results of this work appeared December 13 in the journal Nature, in an article entitled “Origin and Differentiation of Human Memory CD8 T Cells after Vaccination.”

“[Our] longitudinal analysis showed that the memory pool originates from CD8 T cells that divided extensively during the first two weeks after infection and is maintained by quiescent cells that divide less than once every year (doubling time of over 450 days),” wrote the article’s authors. “Although these long-lived YFV-specific memory CD8 T cells did not express effector molecules, their epigenetic landscape resembled that of effector CD8 T cells.”

The study found that the pool of long-term memory T cells is maintained for years after vaccination through the development of several unique features. On the surface and through the actions of their genes, they look like cells that have never been exposed to an infection, but on their DNA the researchers found a fingerprint, called a methylation pattern, that identifies them as having been through battle as an infection-fighting cell.

“These cells are like veteran soldiers, camped in the blood and tissues where they fight their battles, waiting for yellow fever to show up,” said Hellerstein. “They are resting quietly and they wear the clothes of untested new recruits, but they are deeply experienced, ready to spring into action and primed to expand wildly and attack aggressively if invaders return.”

After a first acute exposure to an infectious agent or vaccine, the body has an initial phase with lots of short-lived infection-fighting soldiers, called effector-memory cells. Then after the threat is cleared, effector cells go away and small numbers of long-term memory cells are present. One of the central questions in immunology was whether the long-term memory cells went through an effector stage or went on a separate pathway of their own. The research team found that that a subset of the effector-memory pool that had divided extensively during the first two weeks after vaccination stayed alive as long-term memory cells, dividing less frequently than once every year.

The extremely long life-span of the surviving memory cells allows them to specialize over time into a unique, previously unrecognized, type of T cell. The long-term memory cells have some molecular markers that make them look like naïve cells that have never activated, including a gene expression profile that looks like that in naïve cells, yet have other molecular markers on their DNA of having gone through battle as effector cells.

“These results make it clear that true long-term memory cells were once effector cells that have become quiescent,” Hellerstein asserted. “This apparently keeps them poised to respond rapidly as new effector cells upon re-exposure to the pathogen.

“The combination of molecular evidence of a unique life history with direct measurement of their long lifespan is what gives this study such power. The technology to measure the dynamics of the birth and death of cells and advances allowing it to be applied to very small numbers of cells let this study happen.”








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