Our immune system operates under the basic premise that "self" is different from "non-self." Its primary function lies in distinguishing between these entities, leaving the former alone while attacking the latter. Yet we now know that our guts are home to populations of bacterial cells so vast that they outnumber our own cells, and that these microbiota are essential to our own survival.

As a recent study in Nature Immunology notes, "An equilibrium is established between the microbiota and the immune system that is fundamental to intestinal homeostasis." How does the immune system achieve this equilibrium, neither overacting and attacking the symbiotic bacteria nor being lax and allowing pathogens to get through? It turns out that our gut bacteria manipulate the immune system to keep things from getting out of hand.

Like many stories of immune regulation, this one is a tale of many interleukins (ILs). Interleukins are a subset of cytokines, signaling molecules used by the immune system to control processes such as inflammation and the growth and differentiation of different classes of immune cells. IL-22 is known to be important in defense, both ridding the intestines of bacterial pathogens and protecting the colon from inflammation.

IL-22 is produced by the subset of T cells defined by their expression of IL-17, known as T H 17 cells, as well as by innate lymphoid cells. Sawa et al. report that in the intestine, most of the IL-22 is produced by a specific subset of innate lymphoid cells that live there, and not T H 17 cells.

Microbiota can repress this expression of IL-22 by inducing the expression of IL-25 in the epithelial cells lining the walls of the intestine. The researchers deduced this because IL-22 expression goes down in mice after weaning, when microbial colonization of the intestine dramatically increases. When adult mice were treated with antibiotics, IL-22 production went up again. IL-22 production also increased during inflammation.

Microbiota also induce the generation of T H 17 cells and, even though these normally make IL-22, this induction further depresses its production. The T H 17 ended up competing with the innate lymphoid cells for the same pool of regulatory cytokines; as a result, all of them got less and became less active.

These innate lymphoid cells thus play a critical role in maintaining intestinal homeostasis. They make IL-22, which induces the production of antibacterial peptides by the lining and protects the intestine from pathological inflammation. Symbiotic microbiota make a safe home by tamping down the production of IL-22 by inducing IL-25. The T H 17 cells can contribute to this tamping down by competing for regulators. The authors conclude by stating that “this complex regulatory network demonstrates the subtle interaction between the microbiota and the various forces of the vertebrate immune system in maintaining intestinal homeostasis.”

Nature Immunology, 2011. DOI: 10.1038/ni.2002 (About DOIs).