When Dan Littman was an undergraduate at Princeton University in the mid-1970s, there was no official immunology course. However, one of his virology professors organized a survey course by inviting 20 or so of the leading immunologists in…
When Dan Littman was an undergraduate at Princeton University in the mid-1970s, there was no official immunology course. However, one of his virology professors organized a survey course by inviting 20 or so of the leading immunologists in the world to give guest lectures. For Littman, this was a transformative experience. "I was blown away by the kinds of questions being asked," he recalls. How did the immune system distinguish 'self' from foreign invaders? How is diversity generated in adaptive immune cells? "These were very big questions, obviously," he says. And they tugged Littman toward the study of immunology as a graduate student at Washington University School of Medicine in St. Louis. As a postdoctoral fellow in the lab of HHMI investigator Richard Axel at Columbia University and later as he set up his own laboratory group at the University of California, San Francisco, Littman made key discoveries in T cell biology and in how HIV uses the CCR5 and CD4 receptors on T cells to promote infection. Later, his research group continued to pursue the fundamental questions that had first intrigued him. They were investigating how T lymphocytes decide whether to become helper T cells or cytotoxic T cells when the work took an unexpected turn into a whole new realm—the gut microbiome. Their investigations in this area reveal how our symbiotic bacterial species profoundly influence our immune system's development and responses. Littman's group had been studying whether the transcription factor RORγt, found in immature T cells in the thymus, was important in the developmental decision to become a helper or a killer cell. At about the same time, other researchers found a new type of T cell called Th17 that was responsible for many autoimmune diseases. In collaboration with Dan Cua, at the DNAX Research Institute in Palo Alto, Littman's group found that these cells, which produce IL-17, are most abundant in the gut, where they protect the epithelial barrier lining the small intestine, and are regulated by RORγt. "This took us from studying the fundamental mechanism of T cell development to studying a problem much more relevant to immune function —the recognition of self and non-self," says Littman, now a professor of pathology and microbiology at the Skirball Institute of Biomolecular Medicine at New York University School of Medicine. Littman and his postdoc at the time, Ivaylo Ivanov, noticed that germ-free mice—those born without any gut microbes at all—had no Th17 cells. But if they put back just one strain of bacteria called segmented filamentous bacteria, it induced these mice to develop normal levels of Th17 cells. "We can use this model to study how a single bacterium or a small consortium of strains can regulate the development of the immune system," says Littman. More recently, the team has found that certain gut bacteria also induce other types of lymphocytes in the gut, the innate lymphoid cells, to produce the inflammatory cytokine interleukin-22 (IL-22). Cytokines like this are important for protecting the epithelial surface in the gut—they promote cell growth when there is damage to the lining of the intestine. They also promote the production of anti-microbial peptides by cells. What's emerging from this work is that bacteria influence the immune cells they bump up against in the gut and vice versa. "This is a burgeoning field, driven by the recognition of a dialogue between different constituents in the microbiota and immune system cells," Littman notes. "It's very likely that we have co-evolved with bacteria that give us the 'right' kind of immune system," says Littman. His group is now trying to tease apart the mechanism of how some bacteria seem to flip and trigger autoimmune disease instead. For example, mice lacking RORγt do not develop the IL-17- and IL-22-producing immune cells in the gut and are protected from developing autoimmune diseases that resemble multiple sclerosis and inflammatory bowel disease in humans. Researchers in his group are also colonizing germ-free mice with specific human gut microbes—from patients with Crohn's disease and arthritis—to determine which bacteria are helpful and which are harmful. "It's like we have a giant parasite within us—these 100 trillion cells that outnumber our cells and help to shape our physiology, providing us with functions that we would not have otherwise," says Littman. Finding ways to harness that "alien within us" for good immune health will be his challenge in the future.