The millions of microbes teeming in the gut are known for their exquisite diversity. But according to a new study led by Duke Immunology’s Gianna Hammer, the immune cells in the gut sport a respectable amount of variety as well. The team reported in the October 25 issue of Cell Reports that under conditions similar to inflammatory bowel disease, the diverse functions of seemingly similar immune cells are unmasked.
In a healthy gut, microbe-sensing cells called dendritic cells keep the peace: they present bits of the resident microbes to T cells, along with explicit instructions not to over-react and cause damage. Dendritic cells (DCs) exist in different subtypes and although all DC subtypes are normally peaceful, under conditions reminiscent of inflammatory bowel disease, DCs engage gut microbes in a destructive battle. What Hammer discovered about this battle is that each type of dendritic cell wages a unique battle-plan – as a collective, dendritic cells orchestrate an all-out assault in the gut.
First author Jie Liang and colleagues investigated mice whose dendritic cells (DCs) respond aggressively to gut microbes. In these animals, DCs destroyed the peace by instructing T cells to destroy the lining of the intestine. This type of damage to the intestine is also found in people with inflammatory bowel disease (IBD). A closer look at the complex rules-of-engagement between DCs and T cells revealed a web of relationships that were not apparent in healthy animals. Hammer and colleagues identified three distinct populations of DCs. Two of these uniquely instructed T cells to produce IL-17, a molecule notorious for inflammation. To instruct IL-17-producing T cells one of these DC populations needed the help of MyD88—a sensor of gut microbes—while the other DC subset could do so without it. A third type of DC instructed an entirely different type of T cell—called Th1—to pump out the inflammatory cytokine IFN-g, and also did so without using the MyD88 sensor. Together, the three populations of DCs incited the inflammatory T cells that destroy the intestine, in a destructive battle against gut microbes.
The findings underscore the destructive cellular relationships that come to life in the inflamed gut, and hopefully get researchers one step closer to extinguishing them in people with IBD.