Understanding the Superpower of T-Cell Subtype in Mice and Humans

Scientists at La Jolla Institute for Immunology (LJI) have reported new discoveries about the genes and nutrients that give a T-cell subset known as mucosal-associated invariant T (MAIT) cells some distinctive properties and fighting prowess that might one day be exploited to improve treatments against cancer and infectious diseases.

T cells fight threats by responding to molecular fragments that belong to a pathogen—but only when these molecules are bound with markers that come from your own tissues. For example, an individual’s influenza-fighting T cells can’t help a neighbor, and vice versa. So, most T cells only work in the person who made them.

“However, we all have T cells that do not obey these rules,” said LJI professor and president emeritus Mitchell Kronenberg, PhD. “One of these cell types is mucosal-associated invariant T (MAIT) cells.” In their newly reported work, Kronenberg and his LJI colleagues uncovered another MAIT cell superpower, in that these cells can recognize the same markers whether they come from humans or mice. Kronenberg calls this finding “astounding.” He said, “Humans diverged from mice in evolution 60 million years ago.”

The findings could represent an important step toward one day harnessing these cells to develop more effective infectious disease treatments and cancer immunotherapies. “Because MAIT cells are the same across individuals, they could more easily be used in cell therapies, where, in principle, my MAIT cells could be given to you,” suggested Kronenberg. Gabriel Ascui, a University of California, San Diego (UCSD), graduate student in LJI’s Kronenberg lab, added, “If we could make normal T cells more like MAIT cells, maybe we could make them act faster and more vigorously to combat any type of infection or cancer.”

The team reported on the new findings in Science Immunology, in a paper titled, “Transcriptomes and metabolism define mouse and human MAIT cell populations.”

MAIT cells are a subset of T lymphocytes that respond to microbial metabolites, the authors noted. “MAIT cells are found in humans, mice, and many other mammals.” Kronenberg was initially interested in MAIT cells because of their unexpected response speed. Typical T cells need a few days to develop in the thymus and only adapt to fighting new threats after leaving the thymus—and after several days of stimulation from a pathogen. MAIT cells are much faster because they can respond to more generic markers of infection, rather than hunting for very specific tissue-type markers. For MAIT cells, a red flag is a red flag, no matter who is waving it.

This broad specificity makes MAIT cells similar to the immune system’s first-responder cells, such as macrophages and neutrophils, which make up the innate immune system. “MAIT cells have this ‘innate-like’ characteristic,” explained study co-first author Ascui. “They’re like your first line of defense.” In fact, MAIT cells tend to gather in tissues like the lungs and intestines, where the body is under constant threat from airborne and foodborne pathogens.

The new study showed that MAIT cells don’t just recognize a range of markers within one person. Instead, these T cells can recognize markers shared between humans, and even between species. Scientists refer to these kinds of shared markers as “conserved.” There has been no reason for the markers to change over the eons, so they remain the same across related species.

But just because these MAIT cells look the same between species, doesn’t mean they fight pathogens—or make energy—in exactly the same ways. Comparing human and mouse MAIT cells is important for guiding future studies where mice can serve as useful animal models to study exactly how these cells combat pathogens.

Kronenberg, Ascui, and colleagues used single-cell sequencing and other tools to compare differences in gene expression pathways between human and mouse MAIT cells. “To evaluate the similarities in the transcriptional signatures of human and mouse MAIT cell subsets, we performed integration of the human and mouse datasets,” they wrote. The scientists found that mice have two different kinds of MAIT cells, which produce different inflammatory cytokines. One kind of MAIT cell, which the scientists call MAIT1, produces a lot of the cytokine interferon-gamma (IFN-γ). The other kind of the MAIT cell, called MAIT17, produces a lot of interleukin-17.

A recent Nature Cell Biology study from the Kronenberg lab, co-led by LJI instructor and immunometabolism core director Tom Riffelmacher, PhD, showed that after a bacterial infection, MAIT1 and MAIT17 cells persist but become super-charged, or capable of having greater protective function for months. These cytokines help the MAIT cells take aim at different threats. MAIT1 cells target viruses such as influenza, while MAIT17 cells are better at targeting bacteria.

Through their newly reported study, the team found that MAIT cells from both species are more capable of taking up and storing fat, compared with typical T cells. This finding suggests MAIT cells are more dependent on this nutrient for energy. “Measurement of metabolic parameters indicated that most of the mature MAIT cells had a different metabolic state from most CD8+ T cells, characterized in both species by increased fatty acid uptake,” the scientists stated. “Additionally, the metabolic states of mouse MAIT1 and MAIT17 cells at steady state were strikingly different. In contrast, human MAIT cells were more homogeneous.”

The discovery is in line with previous work in the Kronenberg lab showing that some MAIT cells depend on fat to fight pathogens. The key difference between the species was that human MAIT cells can produce IFN-γ and IL-17, but not evidently by separate cell populations.

The scientists needed to know—was this difference in human and mouse MAIT cells linked to genetic differences or to our different habitats? Lab mice, such as those cared for at LJI, are housed in ultra-clean environments. Their food is blasted in an autoclave to kill pathogens, and their water, toys, and cages are kept as sterile as possible.

Kronenberg and Ascui were curious—do mice living in less-controlled environments show differences in MAIT cell function? “The divergent transcriptional signatures in peripheral MAIT cells might reflect genetic and/or environmental differences between the two species,” they wrote. The team collaborated with UCSD scientists to study MAIT cells from mice kept in so-called “dirty” or less sterile conditions, similar to a pet store environment. “To further understand how the environment can affect the properties of MAIT cells, we have studied outbred mice from pet stores, so-called dirty mice, specific pathogen–free (SPF) controls, and neonatal SPF mice cross-fostered with pet store mothers.” Their results suggested that MAIT cells from these “dirty” mice have even more in common with human MAIT cells, especially when it came to having more MAIT1 cells, which produced more IFN-γ than lab mouse MAIT1 cells.

“Pet stores aren’t dirty in the conventional sense,” says Kronenberg. “But part of the idea is that the ‘dirty’ mice are living in an environment—with more microbes and immune system challenges—that’s a little closer to human environments.”

The team also compared MAIT cells found in different parts of the body, such as the blood, thymus (where T cells, including MAIT cells, develop), and the lung and spleen (where MAIT cells camp out). They discovered that MAIT cells still in the thymus look very similar between humans and mice (“dirty” or not); however, MAIT cells from the lungs and blood are more different between humans and lab mice. “Although mouse and human MAIT cell transcriptomes showed similarities for immature cells in the thymus, they diverged more strikingly in the periphery,” the team stated

MAIT cells from the “dirty” mice fell between the two groups, adding to the evidence that more natural-like environments change how MAIT cells develop and learn to target disease. “Environmental, as well as genetic differences, shape the species differences in these cells,” said Kronenberg. The authors stated, “Undoubtedly, genetic differences between mice and humans influence the frequency and function of MAIT cell populations, but it is also possible that the highly controlled, standard SPF conditions of laboratory mouse housing have an influence as well.”

The new study gives scientists some indication of genetic signatures to tell MAIT cells apart depending on the species and tissues they come from. “Overall, our findings indicated tissue-specific differences in MAIT cell transcriptomes in both species, although preparation of the cell types from different tissues and, for the human subjects, the age and health status were important caveats,” the scientists concluded. Going forward, the team is interested in whether they can prompt typical T cells to express similar genetic signatures. “If we could make normal cells more ‘innate,’ like MAIT cells, perhaps we could improve T cell therapy for cancer,” said Ascui. “That’s one avenue we’re looking at.”

Kronenberg is also interested in whether scientists can modify MAIT cells to actually decrease levels of IL-17 in the body. Although IL-17 helps fight infections, some T cells produce IL-17 against the wrong targets, triggering harmful inflammation and even autoimmune disease.

“There are cases where IL-17 can be a bad actor,” commented Kronenberg. “So although there are cases where we might want to induce more MAIT17 cells, expand their population, we’d also like to find ways to prevent them from arising in situations where they might not be what we want.”