Reins and Spurs for the Immune System

How Disruptions of T Cell Balance Induce Severe Intestinal Inflammation

A finely tuned equilibrium between aggressive and inhibitive immune cells ensures that the intestinal mucosa remains healthy and functional. Scientists at the Helmholtz Centre for Infection Research in Braunschweig, however, have studied on mice what happens when the normal interaction between these cells is disrupted: severe intestinal inflammation, whose symptoms closely resemble human autoimmune diseases, such as Morbus Crohn or Colitis ulcerosa.

"The intestinal surfaces form a border between the insides of the human body and the outside world, and they present our immune system with a monumental task," explains Dr. Astrid Westendorf, a researcher at the Helmholtz center. "Bacteria and other disease-causing pathogens that attempt to penetrate the body must be vehemently repelled at this point," she says. "On the other hand, nutrients, as well as the body's own cells and molecules, must not induce an immune reaction. Otherwise, a severe inflammation could result which might, in the long term, cause serious damage, and in some cases, even destroy the intestinal mucosa."



Dramatic Symptoms

This is exactly what happens with so-called Villin HA-mice, which were studied by Westendorf and her colleagues. "These animals belong to a genetically altered strain that possess a molecule known as hemagglutinin, or HA, on the cells of their intestinal mucosa," she says. Westendorf injected these animals with immune cells from the blood of other mice strains that specifically produced immune cells targeting HA. The result: the immune cells attacked the intestinal surface and induced dramatic symptoms similar to those of patients with chronic intestinal inflammation.



A Surprising Tolerance

When these two strains of mice are cross-bred, however, they produce something astonishing: "The progeny have both the HA on the intestinal surface as well as the special immune cells against HA in their blood, and yet, they remain healthy," notes Westendorf. The reason for this phenomenon, known as "immune tolerance", is probably the so-called regulatory T cells, or TREG , which are specific inhibitors of the immune system that shut down other defense cells before they go too far with their attacks and cause harm to the body. "These TREG must have developed in the animals in the course of their lives," says Dr. Westendorf. They keep the defense cells in check, most of which are the CD4+ or CD8+ type T cells, since these would otherwise attack the always present components of their own intestinal surface.



Complex Interaction

"The constant interaction between aggressive T cells and inhibiting TREG  keeps the immunological balance of our intestinal mucosa intact," explains Prof. Dr. Jan Buer, work group leader at the Helmholtz Centre for Infection Research. "Many chronic, inflammatory intestinal ailments occur because this balance no longer functions," he says. Buer hopes that a better understanding of the processes involved could open up opportunities to selectively turn immune system responses up or down. "That," he says, "could lead to possible therapies for autoimmune diseases, like Morbus Crohn, but also tumors and infections in which the immune reaction needs to be selectively activated."



Original article:

Westendorf A.M.,  Fleissner D., Deppenmeier S., Gruber A.D., Bruder D., Hansen W., Liblau R., Buer J. (2005). Autoimmune mediated intestinal inflammation – impact and regulation of antigen specific CD8+ T cells. Gastroenterology 131(2):510-24



Background: New name for the GBF

As of July 18, 2006, the German Research Center for Biotechnology (GBF) in Braunschweig has been operating under a new name: The Helmholtz Centre for Infection Research. The new name is designed to underscore the main thrust of the research conducted at the institute and to more clearly define the institute's membership in the Helmholtz Association, Germany's largest scientific organization.



Intestinal bacteria at the surface of epithelial cells. Right side: Microvilli of the intestinal mucosa.
Photograph: Helmholtz-hzi/ Kurt Dittmar

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