Scientists at the La Jolla Immunology Institute (LJI) are investigating a talented type of T cell.
Most T cells only work in the person who created them. Your T cells fight threats by responding to molecular fragments belonging to a pathogen — but only when those molecules bind to markers that come from your own tissues. Your flu-fighting T cells can’t help your neighbor’s, and vice versa.
“However, we all have T cells that don’t obey these rules,” says LJI Professor and Chair Emeritus Mitchell Kronenberg, Ph.D. “One of these cell types is mucosa-associated invariant T cells (MAIT).”
Now Kronenberg and his LJI colleagues have uncovered another superpower of MAIT cells: MAIT cells can recognize the same markers whether they come from humans or mice. Kronenberg calls this finding “amazing.” “Humans diverged from mice in evolution 60 million years ago,” he says.
This new research, published in Science Immunology, sheds light on the genes and nutrients that give MAIT cells their fighting power. The findings are an important step toward harnessing these cells to treat infectious diseases and improve cancer immunotherapies.
“Because MAIT cells are the same between individuals, they could more easily be used in cell therapies, where, in principle, my MAIT cells could be given to you,” says Kronenberg.
The new study also opens the door to exploiting MAIT cells to improve cell therapies. “If we could make normal T cells more like MAIT cells, maybe we could make them act faster and more powerfully to fight any type of infection or cancer,” says study co-first author Gabriel Ascui, a graduate student at UC San Diego at LJI’s. Kronenberg Laboratory.
Why MAIT cells are special
Kronenberg was initially interested in MAIT cells because of their unexpected speed of response. Typical T cells take a few days to develop in the thymus and adapt to fight new threats only after they leave the thymus — and after several days of stimulation by a pathogen. MAIT cells are much faster because they can respond to more general markers of infection, rather than chasing very specific tissue-type markers. For MAIT cells, a red flag is a red flag, no matter who waves it.
This broad specialization makes MAIT cells similar to first responder cells of the immune system, such as macrophages and neutrophils, which make up the “innate” immune system. “MAIT cells have this ‘innate’ characteristic,” says Ascui. “It’s like your first line of defense.” In fact, MAIT cells tend to concentrate in tissues such as the lungs and intestines, where the body is under constant threat from airborne and foodborne pathogens.
The new study shows that MAIT cells don’t just recognize a series of markers in an individual. Instead, these peculiar T cells can “see” markers that are shared between people — even between species. Scientists call these kinds of shared markers “conserved.” There has been no reason for the indices to change over the centuries, so they remain the same in related species.
But just because these MAIT cells look the same across species doesn’t mean they fight pathogens — or generate energy — in exactly the same way.
Why look at mouse cells?
Comparing human and mouse MAIT cells is important to guide future studies where mice can serve as useful animal models to study exactly how these cells fight 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. The scientists discovered that the mice have two different kinds of MAIT cells, which produce different inflammatory molecules called cytokines. One type of MAIT cell, which scientists call MAIT1, produces a lot of a cytokine called interferon-gamma. The other type of MAIT cell, called MAIT 17, produces a lot of a cytokine called interleukin-17.
Recent Nature Cell Biology study from the Kronenberg lab, led by LJI Instructor and Core Immunometabolism Director Tom Riffelmacher, Ph.D., shows that after a bacterial infection, MAIT1 and MAIT17 cells persist but become supercharged or capable of greater protective function for months . These cytokines help MAIT cells target different threats. MAIT1 cells target viruses such as influenza, while MAIT17 cells better target bacteria.
In the new study, the team found that MAIT cells from both species are more capable of taking up and storing fat, compared to standard T cells. This finding suggests that MAIT cells are more dependent on this nutrient for energy. This discovery is also consistent with previous work in the Kronenberg lab showing that some MAIT cells depend on fat to fight pathogens. The key difference between species was that human MAIT cells can produce interferon-gamma and IL-17, but not apparently from separate cell populations.
When mice live like us
Scientists needed to know — was this difference in human and mouse MAIT cells linked to genetic differences or our different habitats? Laboratory mice, such as those cared for at LJI, are housed in extremely clean vivariums. Their food is autoclaved 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 team collaborated with UC San Diego scientists to study MAIT cells from mice kept in so-called “dirty” or less sterile conditions, similar to the environment of a pet store. Their research suggests that MAIT cells from these mice have even more in common with human MAIT cells, especially when it comes to having more MAIT1 cells, which produced more interferon-gamma than laboratory mouse MAIT1 cells.
“Pet stores are not dirty in the conventional sense,” says Kronenberg. “But part of the idea is that the ‘dirty’ mice live in an environment — with more germs and immune system challenges — that’s a little closer to the human environment.”
The team also compared MAIT cells found in different parts of the body, including the blood, the thymus (where T cells, including MAIT cells) develop, and the lung and spleen (where MAIT cells camp). They found that MAIT cells in the thymus gland are very similar between humans and mice (“dirty” or not). However, MAIT cells from lung and blood are more diverse between humans and laboratory mice.
MAIT cells from the “dirty” mice fell between the two groups, adding to the evidence that more natural environments change the way MAIT cells develop and learn to target disease.
“Environmental, as well as genetic differences, shape species differences in these cells,” says Kronenberg.
What does this mean for clinical research?
The new study gives scientists a kind of answer key, a list of genetic signatures to distinguish MAIT cells by species and tissues from which they originate. Going forward, the team is interested in whether they can induce typical T cells to express similar genetic signatures.
“If we could make normal cells more ‘innate’, like MAIT cells, maybe we could improve T-cell therapy for cancer,” says Ascui. “That’s an avenue we’re looking at.”
Kronenberg is also interested in whether scientists can modify MAIT cells to actually reduce levels of IL-17 in the body. Although IL17 helps fight infections, some T cells produce IL-17 against the wrong targets, causing harmful inflammation and even autoimmune diseases.
“There are cases where IL-17 can be a bad actor,” says Kronenberg. “So while there are cases where we might want to induce more MAIT17 cells, expand their population, but we’d also like to find ways to prevent them from arising in situations where it might not be what we want.”
Additional authors of the study, “Transcriptomes and Metabolism Define Mouse and Human MAIT Cell Populations,” include first authors Shilpi Chandra and Thomas Riffelmacher and Ashu Chawla, Ciro Ramírez-Suástegui, Viankail C. Castelan, Gregory Seumois, Hayley Simon, Mallory P. Murray, Goo-Young Seo, Ashmitaa LR Premlal, Benjamin Schmiedel, Greet Verstichel, Yingcong Li, Chia-Hao Lin, Jason Greenbaum, John Lamberti, Raghav Murthy, John Nigro, Hilde Cheroutre, Christian H. Ottensmeier, Hedrick, Li-Fan Lu and Pandurangan Vijayanand.