Growing up on a farm in southwestern Australia, Jason Cyster was fascinated by the microbes he saw in pig waste and the diseases some animals suffered. So by the time he went to the University of Western Australia in 1985, he intended to become a biologist. Attracted to immunology because of the university's reputation in that field, he soon made that his career choice. Now he studies the behaviors of the immune cells that recognize and kill disease-causing microbes. His findings might eventually help people with immunological diseases or lead to better immunosuppressants for organ transplant patients.
"I'm driven by a general fascination with how the system works, how we avoid mounting autoimmune responses, and how we fight infection," Cyster says. "But I also believe that improved mechanistic understanding will provide new opportunities for the development of drugs that augment or dampen immune responses."
Billions of white blood cells, or lymphocytes, patrol the body looking for trouble, but only about 1 in 100,000 is able to deal with, say, the virus that causes the common cold. The other 99,999 are equipped to recognize thousands of other pathogens and foreign particles. To ready for action, each white cell must interact with others that spot the same threat. When Cyster established his lab in San Francisco in 1995, little was known about the molecules that organize lymphocytes inside lymph nodes so they can meet and greet other cells of the right type.
It was clear at that time that lymph nodes are divided into "B zones," where antibody-producing lymphocytes called B cells gather, and "T zones," where the lymphocytes that help B cells are found. "But how those cells went to those separate areas was unknown," Cyster says. "We speculated that chemokines might be involved." Chemokines are biochemicals that were known to attract white cells to areas of inflammation, but Cyster and his collaborators discovered ongoing functions as well. For example, they found that a chemokine called CXCL13 attracts wandering B cells to lymph nodes' B zones. Work by several groups, including Cyster's, showed that different chemokines attract T cells to T zones. "The limited number of [chemical] cues needed to organize lymphoid organs was a surprise," Cyster says.
Knowing how B cells and T cells settle into lymph nodes didn't answer the question of how those two cell types meet. But Cyster's group showed that when B cells encounter the right type of antigen—a smidgen of protein from a virus, perhaps—they double their production of a receptor that interacts with T-zone chemokines. Those B cells then migrate to the edge of the T zone and interact with helper T cells, which prompt them to divide and become antibody-producing cells.
Cyster also studies autoreactive B cells, which are involved in autoimmune conditions such as rheumatoid arthritis. After other groups identified a molecule called BAFF that B cells need for survival, Cyster's group showed that autoreactive cells need more BAFF than other B cells. "One suggestion from our study was that partial blocking of BAFF might be sufficient to selectively remove the more autoreactive cells," Cyster says.
Cyster is also tackling another big unknown: how T cells escape from lymphoid organs, such as the thymus, so they can circulate in the body. He gets some of his best ideas by having long brainstorming sessions with people in his lab who are thinking about the same problem. "I find these discussions are most effective when they involve a talented individual who could take a new idea and run with it," he says. "The excitement of knowing this feeds back to motivate uninhibited and potentially creative discussion."
Through such discussions and genetic experiments, Cyster's group discovered that T cells that haven't yet encountered the right type of antigen have a certain receptor for a lipid called sphingosine-1-phosphate (S1P). "And we were able to show that if T cells don't have this receptor, they can't get out of the thymus, so you don't have any peripheral T cells," Cyster explains. "And if you put them in the periphery, they can get into lymph nodes but can't get out. The extent to which lymphocyte egress depends on a single receptor was a surprise."
Cyster says HHMI's support gave him the freedom to pursue basic questions on immune system organization even if they have no immediate clinical relevance. "Most recently, by facilitating the acquisition of a two-photon microscope, HHMI has allowed my lab to turn toward obtaining a truly dynamic understanding of how immune responses unfold in vivo."
His basic research might eventually advance medicine, however. "Our studies may allow the development of more targeted forms of immunosuppression than are currently available," Cyster explains. "This could allow transplant acceptance or dampening of an autoimmune or allergic disease while maintaining sufficient immune function to thwart most infections."
Meanwhile, Cyster will enjoy brainstorming with colleagues. "In research, we are literally following our dreams—the best ideas we can come up with," he says. "That is something that you can only like, and it is something wonderful that I always take as a privilege."