It is hard enough for a body to detect, fight, and defeat all possible pathogens. The immune system also has to worry about some of its extensive troops turning against the tissues they are supposed to defend.
Researchers at Dana–Farber Cancer Institute have discovered a shrewd back-up mechanism that may help keep the peace between the immune warriors and the body. The findings may lead to a better understanding of how the immune system polices itself and how self-tolerance breaks down in autoimmunity.
The first safeguard against rogue immune cells happens as part of making millions of unique T cells daily. A stringent selection process in the thymus destroys most new T cells by screening them against a full assortment of the body’s homegrown proteins.
But the thymus is not perfect. Many self-reactive T cells escape with the pathogen-fighting soldiers. The fugitives have the potential to attack the body’s own tissues and cause autoimmune diseases such as type 1 diabetes and multiple sclerosis. In a second level of precaution, other immune squads posted from head to toe scout for self-reactive T cells as vigilantly as they do for invading microbes.
Until now, dendritic cells seemed to be the sole disciplinarians enforcing the second-line, or peripheral, tolerance among immune cells. As immunology peacekeepers, these sentries display antigens gathered from local tissues, and then they delete or disarm dangerous self-reactive T cells that take their bait. They can also dispatch regulatory T cells programmed to protect specific tissues from their misdirected comrades. All these consultations between circulating T cells and patrolling dendritic cells take place in lymph nodes.
A lymph node wallflower, mostly unnoticed until now, appears to achieve the same results by different means, report Shannon Turley and her colleagues. Stuck in place, stromal cells that provide the structural framework for lymph nodes throughout the body have the unusual ability to make proteins normally found only in specialized tissues and use those antigens to screen out the self-reactive T cells that come along, according to their paper in the February Nature Immunology.
“Stromal lymph node cells, which we previously used to ignore, have some serious influence on the T cell response,” said Turley, HMS assistant professor of pathology at DFCI. “The microenvironment of the lymph node regulates T cell function by means of a cell not previously recognized as interacting with the immune system.”
These stromal cells are concentrated in the node areas where the T cells gather. In a complicated experiment, the stromal cells worked well enough to render a dendritic cell intervention unnecessary.
“We’re not saying dendritic cells don’t participate in tolerance induction,” said Turley, who trained in the Rockefeller University lab of Ralph Steinman, the scientist who in 1973 first discovered dendritic cells and their ability to invoke immune responses. Their tolerance-induction activity was worked out more recently. “We’re saying that another cell type is participating and that dendritic cells are not always required for the process.”
So far, Turley’s team has provided direct functional evidence only in an intestinal self-antigen engineered into a mouse. The animal’s gut expresses the antigen, a chicken egg protein, early enough to be accepted as “self.” The researchers chose the model to explore how dendritic cells manage the constant immune stimulation of intestinal bacteria without triggering more frequent autoimmune attacks on the gut.
Bacteria can turn tolerizing dendritic cells into activating dendritic cells that alert other T cells to multiply and fight. Turley and her colleagues became diverted by their baseline studies to document immune activity in the model. Eventually, their results made their original question a moot point.
In the mice, they found the self-antigen–specific T cell recognition and deletion was happening not only in the gut lymph nodes but in distant skin-draining lymph nodes as well. Kinetic experiments showed this process occurred simultaneously around the body, apparently not starting in the gut and spreading around. To confirm, another experiment eliminated the usual suspects that distribute immune signals—dendritic cells, B cells, and macrophages. And there was no sign of the antigen or activity in the mouse spleens.
What else could be working to delete these self-reactive T cells? The only other possibility seemed to be stromal cells in the lymph node, akin to the antigen-expressing epithelial cells in the gut.
In contrast to dendritic cells, which must eat, digest, and display proteins made by other cells and then hustle out to the lymph node, lymph stromal cells appear to make a full repertoire of proteins in-house, a phenomenon called “promiscuous” gene expression.
In different mice and in people, other naturally occurring tissue-specific proteins are also found in lymph nodes around the body, according to preliminary follow-up studies Turley reported at a recent scientific meeting.
“The body can’t afford to let autoimmune cells escape the thymus and get out of control,” said William Heath, a Howard Hughes international scholar at the Walter and Eliza Hall Institute in Australia. “The finding is exciting because it raises the possibility of a peripheral mechanism of self-tolerance that can induce tolerance to tissue-specific proteins by expression in epithelial cells.”
The thymus contains the only other cells known to do this. Five years ago, a paper from the Joslin labs of HMS researchers Diane Mathis and Christophe Benoist made a big splash with the news that the protein aire prompted the expression in the thymus of many organ-specific proteins such as insulin from the pancreas (see Focus, Oct. 25, 2002). Before that, despite some other evidence of ectopic expression in the thymus, scientists assumed all those proteins had to travel or be carried there. Turley, a co-author of the Joslin paper, found aire in the mouse spleens, but its role there is unclear.
“It’s a new mechanism we didn’t know existed,” said Harald Von Boehmer, HMS professor of pathology at DFCI, who is collaborating with Turley on follow-up studies. “One now understands that mechanisms of tolerance thought to be restricted to the thymus or to dendritic cells can be mediated by stromal cells that apparently, like medullary epithelial cells in the thymus, ectopically express tissue-specific antigens. It may be good to have these stromal cells, which do not lose their tolergenic properties in the presence of bacteria, in the gut where there are lots of bacteria.”
