If innate lymphoid cells are rare, and hence elusive, their precursors are even more so—which is saying something. Lymphoid cells were recognized just five years ago, somehow escaping the notice of scientists who had spent a century busily characterizing the immune system. These scientists, preoccupied with immune cells in the blood, lymph nodes, and spleen, overlooked mucosal barriers such as the bowel and the lung. It is at these mucosal barriers—where the body comes in direct contact with the environment—that innate lymphoid cells (ILCs) dwell. They specialize in the rapid secretion of polarized sets of cytokines and chemokines to combat infection and promote tissue repair.

Not only are ILCs far less numerous than, say, lymphocytes, they are seldom found in the blood. Accordingly, they keep their lineages and developmental pathways well hidden. While ILCs may be inconspicuous, they attracted the scrutiny of a research team at the University of Chicago. The team, led by Albert Bendelac, Ph.D., picked up the trail of ILC precursor cells (ILCPs) by applying relevant knowledge that had been gleaned from work with natural killer cells.

Previous work with natural killer (NK) cells and lymphoid tissue inducer (LTi) cells, the researchers knew, had prompted a provisional classification of all ILCs into groups 1, 2, and 3 on the basis of cytokine properties. Most important, work with NK cells had revealed that ILCs express an unusual transcription factor called PLZF during their development.

To follow up on these clues, the scientists created so-called reporter mice with the gene for green fluorescent protein inserted into mouse DNA, just downstream from the PLZF gene. As a result, cells from those mice that expressed PLZF appear bright green under the microscope.

Even though green-glowing cells stand out, finding the precursors to these lymphocytes, about one in 10,000 cells, was not easy. The precursors are not in the blood, and by the time they migrate to the lungs or gut, they have already matured into ILCs. Nonetheless, the researchers eventually found the precursors to innate lymphoid cells (ILCPs) in the liver of fetal mice and in bone marrow of adult mice.

These results were reported in an article published February 9 in Nature, in an article entitled “A committed precursor to innate lymphoid cells.” The authors wrote: “Our studies have identified the elusive CLP-derived common progenitor to the ILC1, ILC2, and ILC3 lineages and demonstrated close but distinct lineage relationships with classical NK and LTi cells.”

To confirm their findings, the researchers designed mice where PLZF gene expression was tied to the gene for diphtheria toxin. When cells expressed PLZF, they also produced the toxin, which was lethal for those cells. The result was a mouse that had a normal immune system except that it completely lacked innate lymphoid cells.

“ILCs are found in the most exposed tissues,” Dr. Bendelac said. “They are one of your first lines of defense. We now suspect they may also influence the ensuing adaptive immune response, priming the pump, influencing how T-helper cells respond.”

“Our findings provide one more tool for understanding this complex system,” Dr. Bendelac added. “This will help generate powerful new ways to assess the function of innate lymphocytes.”

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