Immunology

Promoting Immunological Self-Tolerance

For more than a decade, says Shannon Turley, PhD, she has had a passion for dendritic cells, the "most potent" of the professional antigen-presenting cells (APCs) involved in adaptive immunity. Not only has she trained in dendritic cell biology, her laboratory in the Department of Cancer Immunology and AIDS has focused primarily on understanding the role of dendritic cells in immunity and tolerance, as well as their implications for autoimmune diseases and tumor immunology. Small wonder, then, that her findings - which challenge the supremacy of the dendritic cell in immune regulation - were hard to believe at first.

Turley and colleagues sought to understand how dendritic cells induce T-cell tolerance to self-antigens in the intestine, which is teeming with microorganisms; little has been known about tolerance induction in organs exposed to the environment. Self-tolerance, which is crucial to preventing autoimmune diseases, is promoted by the immune system through the mechanisms of central tolerance, which takes place in the thymus, and peripheral tolerance, which occurs in secondary lymphoid organs, such as lymph nodes and spleen. As T cells develop in the thymus, they are "educated" to ignore self-antigens; as they enter the circulatory system, peripheral tolerance controls any remaining self-reactive T cells that may have escaped central tolerance. Dendritic cells play a role in both mechanisms by cross-presenting antigen-MHC complexes to T cells. Cross-presentation is the process of internalizing exogenous antigen (which originates from outside the cell), breaking it down, and then coupling it with MHC for display on the surface of the cell.

Lymph node stromal cells stained for smooth muscle actin 

In her study, Turley indeed found dendritic cells in the gut and gut-associated lymphoid tissues. She also found that they cross-present intestinal self-antigens, but are not essential for inducing tolerance. To everyone's astonishment, lymph node stromal cells - previously overlooked in immunological tolerance - were found to promote the elimination of T cells that react to intestinal self-antigen. Moreover, unlike dendritic cells, they do so through direct presentation, the process of displaying endogenous antigens (which originate from inside the cell).

"Lymph node stromal cells actually express these intestinal antigens and present them in MHC complexes in every lymph node of the body," marvels Turley. "As circulating self-reactive T cells brush by, they become functionally tolerized or silenced. We had thought that dendritic cells were the only players responsible for peripheral tolerance," she adds. "Now we know that the stromal cells we discovered are equally, if not more, important."

Follow-up studies from other laboratories have since confirmed Turley's results and reported a much more generalized mechanism of tolerance induction for lymph node stroma. "This was fantastic for us," says Turley. "When we made the first discovery, it was so surprising, so unexpected, that we wanted others to find the same results." Further research from her laboratory and others has shown that these lymph node stromal cells directly present specialized antigens associated with other bodily organs, including the skin, eye, and pancreas, as well as tumors. Today, the Turley laboratory is seeking to understand the molecular underpinnings of this new mechanism of peripheral tolerance, while also investigating the roles that lymph node stroma may play in autoimmunity and tumor immunology.

Turley now sees these stromal cells, which have become a major focus of her laboratory, as a "risk-free" mechanism for promoting tolerance. Dendritic cells, which are exposed to bacteria, viruses, and other pathogens, become immunogenic over time and lose their capacity to induce tolerance. "They can protect us against pathogens, but stromal cells appear to be dedicated to promoting self-tolerance," she explains.