On August 1st, immunologist Kazuki Nagashima joined the MCB faculty. His research program investigates interplay between the gut microbiome, diet, and the immune system.
“I’m delighted that Kazuki is joining our department, and I think that we’re a great match as a scientific home for him to develop his exciting research program,” says MCB Chair Rachelle Gaudet. “On the one hand Kazuki has extensive training in immunology, which brings important new expertise to our department that will strengthen both our research and our teaching curriculum. On the other hand, Kazuki’s research encompasses questions from the protein biochemistry to the organismal level, and he will benefit from many interactions with MCB colleagues that span this broad range of approaches and interests.”
“We are excited to have Kazuki join our community both because of his exceptional scientific accomplishments and the breadth he brings to our mission in research and teaching,” says MCB faculty Richard Losick who chaired the faculty search committee. “Immunology is an important field for MCB, but we haven’t had an immunologist on our faculty in many decades, and Kazuki is excited to contribute to our undergraduate teaching program in this fundamental area.”
Nagashima was born in the Saitama prefecture, a suburban region outside Tokyo to architect parents. The family moved to Tokyo shortly before Nagashima started elementary school. He says the city is a busy place but he loved living there.
As a young child, Nagashima experienced a type of skin inflammation called eczema. Through a process known as “allergic march,” where eczema leads to the development of other autoimmune conditions, Nagashima became allergic to certain foods. “At that point, I didn’t realize that the immune system even exists, but I was curious [about] what is causing the difference between myself and other kids,” Nagashima recalls. His eczema and food allergies eventually subsided, but the early experience left him curious about how the body interacts with factors in the external environment, such as food and pathogens.
After high school, Nagashima enrolled in a six-year program at University of Tokyo that combines undergraduate studies and medical school. He explains that not everyone who goes through the program becomes a medical doctor, but at the time it seemed like the best way to keep his options open later. His medical studies deepened his curiosity about the immune system.
“Before entering medical school, I was actually interested in math and physics,” he recalls. “Biology looked a little bit chaotic, and I thought there were no basic principles. But I learned in medical school, especially by reading a masterpiece of molecular and cell biology, Molecular Biology of the Cell, that biology is coded in the genome. And our central dogma from DNA to messenger RNA to protein is conserved across any organism. And it attracted me to biology by finding that even an apparently chaotic biological system is supported by this basic principle.”
Upon completing medical school, Nagashima joined Hiroshi Takayanagi’s lab at the University of Tokyo, where he pursued Ph.D. in immunology. Nagashima’s research focused on a type of intestinal cells called microfold cells or “M cells” that help form a barrier between the microbiome and immune system. M cells live in immune cell aggregates and are mediators of interactions between the immune system and the microbiome. Nagashima inspected these immune aggregates and identified a previously unknown group of mesenchymal cells. He also found that these mesenchymal cells secrete a cytokine that causes the formation of M cells.
He continued on to a postdoc in Michael Fischbach’s lab at Stanford. Nagashima says he experienced a bit of culture shock moving to California after spending most of his life in Tokyo. He says that in Japan people work too hard. In California, there is a better balance between work and family. “It’s an interesting experience,” he says. “Also moving to a new environment and being inspired by a different atmosphere really helps shape your new science. So I expect that happens again when I move to the East Coast, to Boston.”
One of Nagashima’s accomplishments in the Fischbach lab was developing a complex consortium of gut microbes that can be inoculated into germ-free mice. The consortium includes over a hundred bacterial strains and mimics many of the functions of a wild type microbiome. “In my first author project, I colonized this model microbiome to germ-free mice and identified how individual strains interact with immune cells, especially T cells, in that model gut microbiome,” he says.
T cells play an essential role in either spurring the rest of the immune system to action or calming the inflammatory response. However, very little is known about how T cells recognize bacteria. T cell receptors (TCRs) can bind to a wide variety of antigens, but researchers don’t know precisely which antigens TCRs bind in vivo. “T cell receptors have the potential to bind to any antigen, because every T cell has a different receptor,” Nagashima says. “The receptor diversity is so high, but with this current technology, it’s very hard to identify the target of TCR… Just identifying one target against one T cell receptor takes so much time.”
Nagashima aims to streamline the process of figuring out which antigen a TCR binds. During his postdoc, he developed a high throughput method for doing so. Last year, he published a paper reporting antigens for 92 different TCRs. The result was a significant step forward from papers that report just one antigen, but finding ways to further expedite the process will be a key area of focus for his lab. He says, “The actual diversity of human T cell receptors is so high, and just one hundred is the tip of the iceberg.”
“Kazuki discovered that a subset of immune cells known as ‘T cells’ are unexpectedly dedicated to recognizing bacteria in our gut microbiota,” explains Losick. “They do so by recognizing epitopes (antigens) that are broadly conserved and highly abundant on the surface of bacteria in the human gut. We usually think of T cells as being central to adaptive immunity (which recognizes novel antigens) but these specialized T cells resemble the innate immune system in that they are dedicated to particular antigens.”
Diet is another component that heavily influences the microbiome and immune response. Nagashima is investigating how food shapes immune response through a collaboration with Elizabeth Sattely’s lab at Stanford “People know that food has a huge impact on human health, but no one knows the mechanisms,” Nagashima says. “So we focus on how food induces gut T cells and how food influences our health and disease by activating these T cells.” He plans to continue this research in his new lab, where he and his team will look into what antigens on food are stimulating the immune response.
Experiments exploring the microbiome and immune response require germ-free mice inoculated with known strains. However, there are no germ-free mouse colonies on Harvard’s main campus. Nagashima is partnering with Brigham and Women’s Hospital, which has a large breeding colony of germ-free mice, to obtain adult mice that can be inoculated and housed on campus. He plans to keep using the one hundred strain consortium he developed during his postdoc as a baseline. “By using derivatives of altered communities, we can scientifically compare different functions of gut communities,” he says. “This is very critical for experiments to reproducibly test the function of each strain.”
In addition to mouse studies, Nagashima plans to look into human TCRs by studying gut tissue samples from hospital repositories. He expects there to be some similarities to what mouse TCRs bind but also significant differences.
Nagashima is eager to recruit undergraduates, graduate students, and postdocs to his lab, pointing out that it is one of very few immunology labs on the north side of the Charles River. In his lab, students are not just aiming to publish a paper and get a degree, but are encouraged to value their own ideas so that they can think independently as full-fledged immunologists and conduct research independently. His students will devise new experimental systems that will lead to new principles of biology that no one has yet elucidated.
During his free time, Nagashima often plays soccer. He says that in California, there were opportunities to play even in winter, but he’s not sure if that will be true in Boston. He adds that the combination of science, soccer, and family is more than enough to keep him busy.
Nagashima is looking forward to being part of MCB. “MCB has been such an important and prestigious place for molecular and cellular biology,” he says. “However, at the same time, MCB doesn’t have faculty working on immunology experiments and immune system analysis. So I thought by joining MCB, not only can I learn the depth of biology, I can also contribute by bringing something new.”
