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A T cell’s fate

The immune system responds to pathogens by activating T cells, some of which die while others remember the invaders.

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Healthy humans are born with billions of infection-fighting machines called T cells. We need so many because a T cell exists for virtually every type of virus, bacterium, or parasite. T cells respond to foreign intruders by replicating like mad to generate an army of these defenders, including killer T cells. As the infection clears, millions of those T cells die off. Only 5 to 10 percent remain in the blood, poised to attack like a boxer anticipating a familiar foe’s first punch. These are memory T cells.

“Your immune system gets imprinted physically with cells that are generated during the first infection,” said Susan Kaech, Ph.D., associate professor of immunobiology and a Howard Hughes Medical Institute early career scientist. This is why vaccines are so crucial, she said. The immune system remembers the infectious agent so it can ward off infections immediately, rather than letting nature run its slower (and sometimes fatal) course.

But how do T cells become memory T cells? Scientists had long assumed that the process was random and largely governed by external forces. Research over the past decade, however, suggests that certain T cells may be more intrinsically fit to become a long-lived memory T cell. During a viral infection, some T cells express a receptor designed to detect a cytokine called interleukin-7, and those cells live to fight future infections. Most other T cells do not express that receptor, and they don’t survive.

Yet research also suggests that environmental forces might be at work. The more inflammation T cells are exposed to, for example, the greater their chances of differentiating into killer T cells that can help clear the present infection. This exposure, however, also makes them more likely to die after an infection. In contrast, T cells only mildly exposed to inflammation or to anti-inflammatory signals are more likely to develop into memory T cells.

How such diversity of T cell fates arises remains a puzzle. Are T cells born as either memory or terminal T cells?

“I think that would be kind of scary. It would be like pre-determining the fate of a person while they were still in the womb,” Kaech said, noting that infection is unpredictable, never giving advance warning of which pathogen might strike, when or where it comes from, and how much you’ll be exposed to. In the face of such random events, the immune system must remain pliable. “You don’t know what someone will become before they are born; and similarly, you wouldn’t want your immune system deciding if a T cell was going to live or die before it has even seen the pathogen it recognizes.”