Discoveries
Researchers obtain first 3-D pictures of key phase of human immune response
The immune system's helper T cells determine whether other cells are cancerous or infected by latching onto small pieces of protein on the cells' surface. The images above provide the first threedimensional look at the coupling of a helper T cell (part of whose "docking equipment" is shown in blue) and a protein fragment (shown in yellow). The white structure is a class II major histocompatibility complex, which serves as a tiny "holder" for the protein fragment.
Scientists have long known that the immune system's "helper" T cells identify cancerous or infected cells by latching onto the cells and probing protein fragments displayed there. If the fragments, called peptides, indicate the cell is diseased, the T cells order an immune attack to have it destroyed.
Now, thanks to a laboratory team at Dana-Farber, researchers have the first close-up pictures of helper cells conducting their protein interrogation.
The pictures, made with a process known as X-ray crystallography, suggest that helper T cells bind to a relatively small portion of the fragments and do so at a perpendicular angle. The finding means scientists can now focus on precisely that area when studying how helper T cells recognize infected or cancerous cells, and may even lead to novel ways of vaccinating people against diseases to which they are genetically prone.
The images were published late last year in the journal Science. They provide a detailed, three-dimensional view of helper T cells' docking equipment — or "receptors" — bound to peptides inside tiny "holders" called class II major histocompatibility complexes. This is the crucial interaction by which T cells determine whether other cells are normal and need to be left alone, or are diseased and should be destroyed.
"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," according to the study's lead authors, Ellis Reinherz, M.D., and Jia-Huai Wang, Ph.D., of the Institute's Department of Cancer Immunology and AIDS.
The study may point the way to a new form of vaccination — called thymic vaccination — that "trains" helper T cells to fight 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 — which are to be left unharmed — and those of unwanted intruders — which are to be destroyed.
If a genetic screening of a newborn determined the infant to be at 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.
The new study gives impetus to the development of such techniques because scientists now know precisely which section of the peptide would need to be altered to create such a variant: the relatively small section that is the target of the T cell receptor.
The current investigation was done with the support of the National Institutes of Health by a team of Dana-Farber researchers, 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. They 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.