The T cell ignition switch
Related story: The immuno man
“Ellen Richie, my friend and colleague from graduate school, was having a lot of fun studying T cells,” he recalls. “She urged me to get into them, which recently had been discovered and were poorly understood.”
Richie, today a professor in Molecular Carcinogenesis at Smithville, is an expert on the development of T cells and the thymus — an organ right behind the sternum where these white blood cells mature.
“Somehow, something I said raised his interest in T cells, but I don’t recall specifics,” Richie says. “I’m really glad that it did, though, because he revolutionized the field.
“From his earliest days, he was always on the cutting edge,” she says. “He was never shy or put off by common wisdom or existing methods, challenging them when he found evidence to the contrary. He’s persistent — he definitely doesn’t give up.
“The big mystery of the time was the T cell antigen receptor. Nobody had any idea what it was,” Richie says. “The intellectual challenge that presented itself appealed to Jim.”
T cells seemed to function in a way that required them to recognize an antigen — a distinctive piece of a virus or bacterium, for example — to become activated and attack the invader. Research to identify a T cell antigen receptor had been so plagued by lack of conclusive proof that some scientists thought it might not exist at all, that T cells worked by some other mechanism.
Cancer and the Immune System
Allison recalls a graduate-level immunology textbook that closed with some advice for budding immunology researchers: “Don’t try to find the T cell antigen receptor because it’s ruined more careers and wasted more time than any other single thing.
“So we tore that page out and stuck it to the wall in our lab because we figured we already had it, or at least an antibody to it.”
In a 1982 paper in the Journal of Immunology, Allison and colleagues identified an antibody that bound only to a specific type of lymphoma cell. Its specificity was a surprise — it didn’t connect with any other lymphoma cell line or with normal spleen, thymus, lymph node or bone marrow tissue.
Intrigued, they tapped their biochemistry expertise to determine the underlying protein structure on the lymphoma cell surface that held the antigen. Then they looked for similar proteins on the surfaces of other types of cells, finding them only on T cells and their precursor cells, but not on the better-known immune system B cells or in the bone marrow.
Their findings suggested that the protein complex made up a T cell-specific surface structure with both constant and variable regions, ideal for acting as the versatile, longsought T cell antigen receptor.
After publication, the young scientist was invited to a Gordon Conference on immunology, an elite meeting of the leading researchers in the field. A major paper in Cell soon confirmed what Allison’s team had suggested.
“The T cell antigen receptor is the ignition switch of the immune response,” Allison explains. But it wasn’t enough to fully ignite immunity by itself.
“Immunotherapy is the most exciting and promising area of cancer research today, and its potential is just beginning to be realized. We’re proud to have Jim leading our efforts to expand and hone this approach.”