Immunology

T.L. Walunas, D.J. Lenschow, C.Y. Bakker, P.S. Linsley, G.J Freeman, J.M. Green, C.B. Thompson, J.A. Bluestone, "CTLA-4 can function as a negative regulator of T-cell activation," Immunity, 1:405-13, 1994. (Cited in more than 40 publications as of February 1996) Comments by Jeffrey A. Bluestone, University of Chicago, and Craig B. Thompson, Howard Hughes Medical Institute, University of Chicago TURN-OFF:Jeffrey Bluestone hopes to understand how the immune system shuts itself down. In this paper, Jeffrey Bluestone and his collaborators at the University of Chicago, along with colleagues at New York-based Bristol-Myers Squibb Co. and Harvard University, examined the role of CTLA-4, an immune system protein. "CTLA-4 was of interest because it was a homolog-a gene with the same structure, chromosomal location, ligands-of a molecule called CD28," explains Craig B. Thompson, a professor of medicine and a Howard Hughes Medical Institute investigator at the University of Chicago. CD28 has intrigued immunologists because of its role in augmenting the body's immune response through the T-cell receptor. According to Thompson, "CTLA-4 has become the prototype of what's known as a 'co-stimulatory receptor,' a protein necessary to activate T cells." He explains that many scientists believe that in addition to an antigen, immune system cells such as B and T cells need other signals to become turned on. OPPOSITES ATTRACT: Craig Thompson helped reveal the surprising truth about two proteins. While both CD28 and CTLA-4 are located on the T-cell surface, the latter's precise job was unclear. In this work, Bluestone-Charles B. Huggins Professor at Chicago and director of the Ben May Institute for Cancer Research-and his coworkers created monoclonal antibodies against CTLA-4, and used them to stimulate or block the CTLA-4-receptor-activated T cells to study what CTLA-4 does. They were surprised to find that CD28 and CTLA-4 actually had opposite functions. "It was difficult to convince people that these two molecules that had similar binding specificity had such different functions," comments Bluestone. "This paper has been highly cited because it was the first paper that suggested that CTLA-4 did not act like CD28 but in fact acted in the opposite manner," Thompson says. "CD28 is required to turn on the immune response; CTLA-4 is needed to turn off for the immune response." Subsequent research by other scientists reported in M.F. Krummel et al., Journal of Experimental Medicine, 182:459-65, 1995, and in J.G. Gribben et al., Proceedings of the National Academy of Sciences, 92:811-5, 1995, confirmed the findings. Two groups, including one involving Thompson and another involving Bluestone, subsequently created knockout mice that did not have a CTLA-4 gene. In these reports (P. Waterhouse et al., Science, 270:985-8, 1995 and E.A. Tivol et al., Immunity, 3:541-7, 1995), the investigators demonstrated that a mouse without a CTLA-4 gene died after four weeks. "The mouse looks normal at birth with normal lymphocyte numbers, but it is actually destroying its internal organs because of T-cell activation, which [without the gene] it can't turn off," says Thompson. The research may have important implications for understanding immune-system functioning. "Over the last 30 years we've been concerned with trying to understand what turns on the immune system," Bluestone notes. "In the last five years, we've actually become more savvy in understanding what regulates the immune system and shuts it down. It's changed how we think about the immune system. It's highly regulated-it's turned on and then actively regulated back down again." The articles listed here, all less than two years old, have received a substantially greater number of citations than others of the same type and vintage, according to data from the Science Citation Index¨ of the Institute for Scientific Information, Philadelphia. Why have these research reports become such standouts? In conversations with The Scientist, the authors attempt to provide an answer.

Immunology

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