WIKIMEDIA, NCIAt birth, the human body is brimming with naive T cells, immune cells generated in the thymus that have yet to encounter a pathogen. Production of these cells declines with age, but they persist in the body to muster an immune response against novel invaders. In a Science Immunology paper published today (December 2), Columbia University researchers explore the mechanisms behind such persistence, showing that these cell populations are sequestered in lymphoid tissue and that each lymphoid site maintains a unique set of naive T cell clones.

“It’s really nice to have this in the human and across all of these different tissues. [The authors] confirm many of the things that were established in different models,” said Janko Nikolich-Zugich, an immunologist and gerontologist at the University of Arizona who was not involved with the research. “The compartmentalization [of naive T cells] is the biggest story.”

Previous studies...

“After the teams come to get organs for lifesaving transplantation, we come in at the end and get organs and tissues for research,” explained coauthor Donna Farber, an immunologist at Columbia. “We’ve been doing this for almost six years now, so we’ve got donors from infancy to old age. It’s allowed us to ask questions about how your immune system changes or is maintained over the course of a lifetime.”

Naive T cells freshly produced from the thymus are marked by the presence of extrachromosomal DNA, which is gradually diluted out of the cell population with each division. By tracking these markers, Farber and colleagues demonstrated that various lymphoid sites from a single donor accumulated new naive T cells, to varying degrees. “The thymus is pumping out new T cells, but they don’t go everywhere,” said Farber. “They may go where they’re needed more. We don’t know what drives that.”

The team also saw that the level of new naive T cells in lymphoid sites sharply declined in donors older than 40, around the time the thymus started to atrophy. As thymic production fell, however, naive T cells were still maintained in various lymphoid tissues.

The decline in thymic production of naive T cells after age 40 has been suggested in previous work using blood samples, and studies on mouse models have indicated lymph nodes are key for naive T cell maintenance. These latest results confirm previous findings, said Nikolich-Zugich. “The information is great, both technically and conceptually,” he added.

Notably, the team also discovered that the clonal populations of naive T cells—identified by their unique receptors—were compartmentalized in different lymphoid sites with very little migration or overlap.

“This would mean that naive cells ‘build a nest’ at a particular site but do not travel around,” Cornelia Weyand, an immunologist at Stanford University who was not involved in the study, wrote in an email to The Scientist. “The community has always assumed that naive cells are highly mobile, traveling around in an effort to find antigens.”

“It suggests that the naive T cells are getting some signals from the tissue that allow them to persist and expand a bit, but it’s a site-specific phenomenon,” said Farber. She posited that the naive T cells seen circulating in high numbers during childhood are simply those cells in transit to their lymphoid homes, coming from new generation in the thymus. Her team plans to next investigate how and why naive T cells from the thymus are seeded to different tissues.

The compartmentalization of naive T cell populations also suggests that immune reactions may be more localized as we age, and could have clinical implications for targeting vaccines or immunotherapies—which depend on naive T cells seeing the antigens—to specific areas.

“This is definitely one of these very cool studies that expands the horizons of human immunology, gives us all of the right techniques, and brings new information,” said Nikolich-Zugich. “Going forward, it will stimulate work to figure out what this means functionally and how we can further exploit this in therapy.”

J.J.C. Thome et al., “Long-term maintenance of human naive T cells through in situ homeostasis in lymphoid tissue sites,” Science Immunology, doi:10.1126/sciimmunol.aah6506, 2016.

Clarification (December 2): This article has been updated to note that previous mouse model research has shown that lymph nodes are involved in naive T cell maintenance.

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