ABOVE: An immunofluorescence image of T cells (white) in the mesenteric adipose tissue accumulating in lymphoid structures and within interstitial spaces during infection. The vascularization of these lymphoid structures is also highlighted (purple). AGNIESZKA KABAT AND EDWARD PEARCE

Fat cells play a surprising role in combating parasites, according to a study published today (October 14) in Science Immunology, which finds that fatty tissue surrounding the intestinal tracts of mice helps eject gut-infesting worms and fight future infections.

Jorge Caamaňo, an immunologist at the University of Birmingham who was not involved in the work, says that “the study brings to focus the idea that when we’re looking at the immune response, we shouldn’t just focus on” immune cells.

The unexpected discovery of parasite-fighting fat

Scientists already knew that mesenteric adipose tissue—the fat that lines the intestines—contributes to the immune response to pathogens and cancer. But its role in fighting parasites wasn’t well-defined until study coauthor and immunologist Edward Pearce and his colleagues at Johns Hopkins Medical Institute examined how fat cells and immune cells each respond to parasitic infection. 

Pearce’s group was studying how animals gain immunity to such infections in a mouse model when, during a routine autopsy, a veterinarian on the team noticed that the mesenteric adipose tissue of mice infected with parasitic helminths (Heligmosomoides polygyru) stiffened over the course of an infection. Helminths are microscopic worms that infect the gut (and only the gut), leeching nourishment from their host. In mice, they’re used to model human parasitic infections.

The researchers then sought to determine the cause of the tissue stiffness. As they were investigating how different cell types in the tissue responded to infection, they discovered a previously undescribed communication between two cell types that they later found to be important for long-term immunity to parasites: Th2 cells, a type of T cell known to fight parasites, and stromal cells, which are stem cell-like cells found in fat tissue that can differentiate into cells that provide structural support for tissues.

The researchers first isolated the stiffened fat tissue from parasite-infected mice and normal fat tissue from their healthy counterparts. They then separated the tissue into its component cells. And to study how infection restructures the immune cells and structural cells in the tissue, the team employed a combination of single-cell RNA sequencing, flow cytometry, cell culture, and histology.

Their first observation was that in addition to their presence in the gut, Th2 cells infiltrated the animals’ adipose tissue during infection—which the researchers found surprising, says Pearce, “because this infection actually never gets into the adipose tissue. It stays in the gut.”

Then, the team found that these fat-infiltrating immune cells differ from typical Th2 cells, as they were releasing the powerful cytokine TGFβ as well as Amphiregulin, a molecule that stimulates wound healing. They were also activated differently. Instead of being activated by a T cell receptor, a protein complex that typically triggers T cell activity during infection, the Th2 cells identified in the study were activated by cytokines. “They behaved in a way like cells that are part of the innate immune system rather than the adaptive,” says Pearce. 

The researchers then cultured the stromal cells and discovered they became highly metabolically active in response to Amphiregulin and TGFβ produced by Th2 cells. The stromal cells also started to produce cytokines, which further activated Th2 cells as they fought the helminth infection. The researchers also blocked the Amphiregulin receptor EGRF in stromal cells and observed that the severity of infection increased, highlighting the importance of stromal cell activation in fighting infection. 

When the researchers took a closer look at the animals’ tissues, they realized Th2 cells and stromal cells were meeting up in special spaces in the tissue called interstitial spaces, which become enlarged during infection. There, Th2 cells triggered stromal cells to secrete collagen and extracellular matrix, resulting in the observed tissue-stiffening. 

The team also found that some of these changes are long-lasting. Though their tissues returned to normal stiffness shortly after infection, the mice still had elevated levels of Th2 cells for up to a year after their initial infection was cleared with a drug (the mice were infected with the parasite for 11 to 14 days). Th2 cells and stromal cells also mobilized more quickly in response to subsequent infections.

Though Pearce and his team are not quite sure why Th2 cells are invading adipose tissue in the first place, they intend to find out. 

The findings from the study could help scientists fight disease—and not just parasitic infections, says Pearce. The rapid softening seen after a parasitic infection stands in contrast to other diseases where tissue becomes stiffer over time, like fibrosis. “There are strong resolving mechanisms at work here. And if we can understand more about those, perhaps they can be used to treat the type of fibrosis that goes too far.”