For years, scientists studying the immune system have based their observations on snapshots of isolated cells and tissues. Now, thanks to emerging technologies, researchers can have front-row seats to the dance of immune cells occurring within living tissues.
New research, reported in three papers in today's issue of the journal Science, for the first time visualizes the behavior of immune cells and their targets in intact lymph nodes.
The publications open the door to important new discoveries that were not possible using previous techniques.
“It is ‘The Immune System: The Movie’,” says Ronald Germain, M.D., Ph.D., deputy chief of the laboratory of immunology at the National Institute of Allergy and Infectious Diseases (NIAID) and a principal author of one of the studies. “We can now follow individual T cells within intact tissues to observe how they behave and interact with other cells as immune responses develop.”
Much of our current understanding of the interplay among immune cells and their targets has been inferred from looking at chemically stained cells in thin slices of tissues observed under a microscope. Video microscopy has been used to observe the movement of cells, but its use has been limited to small samples grown in culture.
In the three new papers, researchers use two types of microscopes that can scan through a thick sample and limit their focus to living cells lying deep within the lymph nodes, the structures in the body where immune cells are activated in response to microbial invaders or other signals.
According to Dr. Germain, the new technique will permit investigators to explore questions they previously could not clearly address: for example, how long do T cells remain in contact with their target cells, when do the T cells divide, and where do different types of T cells go once they have been activated.
The study by Dr. Germain and his colleagues examined how T cells interact with dendritic cells within lymph nodes. Dendritic cells are key components of early immune responses that mop up invading microbes, display fragments of those microbes to T cells, and help trigger the T cells to respond.
Contrary to what some researchers previously believed, Dr. Germain’s team, with the support of NIAID’s biological imaging facility, showed that individual T cells remain in contact with dendritic cells for prolonged periods.
After that time, the T cells become activated, separate from the dendritic cells and migrate away. The study provides a new glimpse into key steps in early immune responses and paves the way for future work on T-cell activation.
A photograph and brief video of the interacting cells can be viewed online at this URL.
NIAID also funded another group of researchers who used a similar but more powerful type of microscopy to study how immature T cells, which reside in an organ called the thymus, interact with other thymic cells that support their maturation.
Ellen Robey, Ph.D., and coworkers at the University of California at Berkeley and Stanford University showed that many of the immature T cells moved about extensively and formed both long- and short-term complexes with other cells in the thymus.
They found that the length of time immature T cells remained in contact with other thymic cells increased when those thymic cells carried surface proteins that helped the T cells mature. Their study reveals the diversity of interactions that help regulate T-cell development and opens new questions as to when and why the different interactions occur.
In the third paper, researchers from the University of California at Irvine compared T cells and B cells as they moved about within lymph nodes.
In a collaborative study directed by Michael Cahalan, Ph.D., and Ian Parker, Ph.D., the scientists studied how the speed and direction of the cells changed in response to an encounter with an antigen on another cell membrane.
The researchers discovered that T cells traveling about in a random manner switched to a swarming behavior and formed stable clusters following antigenic challenge. That study, which was funded by the National Institute of General Medical Sciences (NIGMS), reveals properties of T- and B-cell behaviors that are critical for initiating immune responses.
NIAID and NIGMS are components of the National Institutes of Health (NIH). NIAID supports basic and applied research to prevent, diagnose, and treat infectious and immune-mediated illnesses, including HIV/AIDS and other sexually transmitted diseases, illness from potential agents of bioterrorism, tuberculosis, malaria, autoimmune disorders, asthma and allergies. NIGMS supports basic biomedical research that increases understanding of life processes and lays the foundation for advances in disease diagnosis, treatment, and prevention. The Institute's programs encompass the areas of cell biology, biophysics, genetics, developmental biology, pharmacology, physiology, biological chemistry, bioinformatics, computational biology, and minority biomedical research and training.
Stoll S et al. Dynamic imaging of T cell-dendritic cell interactions in lymph nodes. Science 296:1873-6 (2002).
Bousso P et al. Dynamics of thymocyte:stromal cell interactions visualized by two-photon microscopy. Science 296:1876-80 (2002).
Miller MJ et al. Two-photon imaging of lymphocyte motility and antigen response in intact lymph node. Science 296:1869-73 (2002).
[Contact: Sam Perdue]