December 2, 1999
Researchers obtain first three-dimensional pictures of key phase of human immune response
Images disclose 'rules of engagement' for T cell attack on infectious agents
The first detailed pictures of key immune system cells locked onto fragments of a foreign substance - published in the December 3rd issue of Science by researchers at Dana-Farber Cancer Institute - provide new clues about how the immune system identifies enemy threats and may even lead to a novel way of vaccinating people against diseases to which they are genetically susceptible, scientists say.
The three-dimensional images, obtained by a process known as X-ray crystallography, show that the cells' docking equipment - or "receptors" - bind to the protein fragments in a manner not previously recognized. The receptor binds to a relatively short portion of the fragment - a process that holds true whether the fragment is from a virus, fungus, bacterium, or a cancer cell. The finding means that scientists can now focus on precisely that area when studying how the cells recognize harmful intruders and bring about their destruction.
"By understanding this fundamental aspect of the human immune response to foreign proteins, we'll gain insights into disorders such as autoimmune diseases and immunodeficiency conditions. We'll also be a step closer to developing new ways of training the immune response to fight specific disorders, including infectious diseases and cancers," say Dana-Farber's Ellis Reinherz, M.D., and Jia-huai Wang, Ph.D., the study's chief authors.
The study involves immune cells called CD4 T cells - also known as "helper" T cells - whose job is to detect foreign invaders and organize an immune system attack against them.
CD4 T cells are alerted to the presence of infection by features known as antigens that are carried by invading bacteria and viruses. When a cell becomes infected, it displays these antigens on its surface, as if to proclaim its distress to the immune system. The antigens, which are comprised of peptides (strings of amino acids), are displayed inside tiny "holders" called major histocompatibility complexes (MHCs).
There are two types of MHCs. Class I MHCs hold relatively short peptides that are "read" by CD8 T cells, better known as "killer" T cells. When the peptides inside an MHC class I indicate a cell contains a dangerous virus or bacteria or is in danger of becoming cancerous, it will be killed by a CD8 cell.
Class II MHCs hold much longer strings of peptides, which are read by CD4 T cells. When the CD4 cells find foreign or ominous-looking peptides, they trigger an immune response by secreting inflammatory messengers and recruiting additional types of cells, including CD8 T cells, that destroy the infected cell.
The Dana-Farber team has obtained the first close-up, three dimensional images of the coupling between the CD4 T cell receptor (or TCR) and peptides ensconced in a Class II MHC. The pictures suggest that no matter what peptide is involved, the TCR will always bind to it on the MHC holder with the same orientation.
For one, the images indicate that the CD4 TCR always docks on top of, and at right angles to, peptides, much as construction cranes may be lowered perpendicularly to grasp an iron beam. Not only that, but no matter how long the peptide is, the TCR on CD4 cells always covers the same, small portion, involving just eight or nine amino acids. Of those amino acids, five or six help anchor the peptide to the MHC, leaving only three or four that are actually in contact with the TCR.
(Earlier work by the Dana-Farber team, as well as Ian Wilson Ph.D., and Don Wiley Ph.D., of Scripps and Harvard universities, respectively, defined the docking mode of TCRs on CD8 T cells and showed that the orientation was more diagonal than perpendicular, although apparently with more variability than predicted for the TCRs associated with CD4 cells.)
The discovery provides immunologists with a precise target of where to focus their studies of CD4 T cells and their interactions with the body's other cells, the investigators say
The implications of the research extend far beyond their utility to researchers. Many of the diseases humans suffer from - from infectious diseases like AIDS and hepatitis to genetic diseases like cancer - involve, to some degree, problems with CD4 T cells. When CD4 cells are overaggressive and attack healthy cells along with diseased cells, the result can be autoimmune diseases such as diabetes mellitus, multiple sclerosis, and rheumatoid arthritis. When CD4 cells fail to sound an alarm about diseased cells, the result is immune deficiency that can leave people vulnerable to infections and cancer. Knowing the precise mechanism by which CD4 cells link up with antigens - and how that mechanism can go awry - can provide new insights into the understanding of these and other diseases.
Beyond that, the study points the way to a new form of vaccination - called thymic vaccination - that "trains" CD4 T cells to be on the lookout for diseases to which individuals are genetically susceptible.
T cells are produced in the thymus gland (hence the "T") during the first year of life. During that time, they're "educated" to distinguish between the antigens of normal cells (so-called self antigens) - which are to be left unharmed - and those of unwanted intruders (so-called foreign antigens) - which are to be destroyed.
If a genetic screening of a newborn determined that the infant was as risk for a certain disease - say breast or prostate cancer as an adult - doctors could potentially alter the child's repertoire of T cells to increase those that are capable of recognizing such tumors and killing them before clinical disease develops, researchers say.
To encourage T cells that recognize a particular peptide to come out of the thymus, doctors could give an infant a slight variant of that peptide, which the T cells would learn to perceive as normal - or 'self' - and leave alone. But they would be sensitized to the slightly different disease-causing peptides and destroy any cells displaying them, investigators say.
The new study gives impetus to the development of such techniques because scientists now know precisely which form the peptide would need to be altered to create such a variant: the relatively small section that is the target of the TCR.
This futuristic technique may not be limited to newborns. By creating an "artificial thymus" and implanting it in a patient's skin, doctors could potentially achieve the same vaccination effect in adults.
The current investigation was done under support of the National Institutes of Health by a team of researchers at Dana-Farber Cancer Institute including Kemin Tan, Ph.D., Lei Tang, Ph.D., Petra Kern, Ph.D., Jin-huan Liu, Ph.D., Yi Xiong, Ph.D., Rebecca Hussey, Ph.D., Alex Smolyar, Ph.D., and Hsiu-Ching Chang, Ph.D., in addition to Reinherz and Wang. Moreover, these investigators collaborated with two Harvard Medical School scientists, Brian Hare, Ph.D., and Gerhard Wagner, Ph.D., as well as scientists at Argonne National Laboratories, Andrzej Joachimiak, Ph.D., and Rongguang Zhang, Ph.D.
Dana-Farber Cancer Institute is a principal teaching affiliate of Harvard Medical School and is one of 35 federally designated Comprehensive Cancer Centers and one of 12 designated AIDS research centers in the United States.
