Immunology

Edited by: Karen Young Kreeger MAKING A MIGHTY MOUSE: Yale's Richard Flavell and coworkers developed a CD40 ligand-less knockout mouse. J.C. Xu, T.M. Foy, J.D. Laman, E.A. Elliott, J.J. Dunn, T.J. Waldschmidt, J. ore, R.J. Noelle, R.A. Flavell, "Mice deficient for the CD40 ligand," Immunity, 1:423-31, 1994 (Cited in more than 80 publications as of August 1996) Comments by Richard A. Flavell, Howard Hughes Medical Institute, Yale University School of Medicine To more closely investigate the role of cell surface receptors in the human immune response, scientists at Yale University genetically engineered a knockout mouse without the gene for CD40L, a ligand molecule that binds to CD40. They designed these mice in collaboration with investigators at Dartmouth Medical School and the University of Iowa Medical School. "The molecule CD40 is found on many antigen-presenting cells, although it was initially thought to be only on B cells," says Richard A. Flavell, chairman of the section of immunobiology in the Yale University School of Medicine and a Howard Hughes Medical Institute investigator. "One thing that the paper shows, from a genetic standpoint, is that CD40L is required to direct a T cell-dependent antibody response," remarks Flavell. This finding in itself, he states, "clearly establishes one action of the CD40 ligand in the immune response. "A second aspect of the paper is associated with a human immune system disease known as the hyper IgM syndrome, or HIM. People with this condition are also deficient for CD40L. Our knockout mouse provides an animal model for that syndrome." In short, Flavell points out, the main observation described in the 1994 paper is the demonstration that T cells from the mice are unable to help B cells make antibodies. These mice therefore show a number of deficiencies that are all linked to the lack of a CD40 ligand. Flavell credits the frequent citation of the 1994 Immunity paper to the rapidly accumulating knowledge about CD40 and its ligand. In subsequent papers (I.S. Grewal et al., Nature, 378:617-20, 1995; P. Borrow et al., Journal of Experimental Medicine, 183:2129-42, 1996; Y. Wu et al., Current Biology, 5:1303-11, 1995; T.M. Foy, J. Exp. Med., 182:1377-88, 1995; I.S. Grewel et al., Science, in press; J.K. Whitmire et al., Journal of Virology, in press), "we've gone on to show that the mice have additional deficiencies that were not predicted from the CD40 T cell-B cell interactions we first described," he says. "What we now know is that in addition to what we described in the first paper, CD40 is also required for T cell function. In other words, the T cell talks back to the B cell via CD40. We also now know that the T cell-B cell interaction is required to activate macrophages, another immune system cell. In order to get the macrophage to perform its essential function, it requires a signal from CD40, and that signal comes from a T cell that expresses the CD40 ligand [R.D. Stout et al., Journal of Immunology, 156:8-11, 1996]. "That's a crucial step in activating a macrophage to kill an intracellular pathogen, for example," he notes. "Imagine a macrophage infected with the tuberculosis bacterium. It probably needs that CD40 signal to kill the intracellular pathogen. We have shown that for leishmania in another paper published this year [L. Soong et al., Immunity, 4:263-73, 1996]. "The CD40-ligand interaction was originally thought to be a T cell-B cell requirement exclusively, but we now know it's also required for a T cell-macrophage; and almost certainly a T cell-dendritic cell interaction [I.S. Grewal, R.A. Flavell, Immunology Today, in press]. We now believe that these are obligate interactions at two stages in the immune response-at activation of the response and in the delivery of effecter functions, for example the mobilization of macrophages."

Immunology

The Scientist Staff

Interested in reading more?

Become a Member of