Reporting in the Aug. 25 issue of Nature, researchers at The University of Texas M. D. Anderson Cancer Center found that Hassall's corpuscles produce chemical signals that instruct dendritic cells in the thymus to induce development of these regulatory T cells - the critically important immune system cells that patrol the body looking for "bad' T cells that can produce autoimmune disease.
"These mysterious little structures in the thymus are responsible for producing the T cell policemen that our bodies depend so heavily on," says the study's lead author, Yong-Jun Liu, M.D., Ph.D., professor and chair of the Department of Immunology. "It is a very smart system that evolved during evolution to efficiently keep the immune system in check."
The thymus functions like a school to educate immature immune system "T" (for thymus) cells. T cells are white blood cells that play vital roles in the immune system, including the identification of specific foreign "antigens" in the body (toxins, bacteria, viruses and other invading cells) and the activation and deactivation of other immune cells.
A chief function of the thymus is the selection of the T cell repertoire the immune system uses to combat infections - a process known as "clonal selection theory" that earned the researchers who discovered it a Nobel Prize in 1960. This involves the "positive selection" of T cells that are non self-reactive and the elimination, through "negative selection," of T cells that are self-reactive or autoreactive. If allowed outside of the thymus gland, these autoreactive T cells would produce a harmful immune response against the body's own tissues, so the immune system flags "dendritic" cells within the thymus to eliminate these bad cells. T cells that pass both levels of selection are then released into the bloodstream to perform vital immune functions.
"It was believed that the only way to induce what is known as central tolerance was by deleting harmful T cells during development," says Liu.
But scientists now know that not all the "bad" T cells are destroyed through negative selection. Some autoreactive T cells escape the thymic censorship process and are released into the circulation. For that reason, researchers searched for additional mechanisms that exist in the blood and lymph system outside of the thymus to take care of these bad actors - which led to the discovery of regulatory T cells. These special T cells act like policemen to scour out dangerous T cells and suppress activation of the immune system, and thus maintain tolerance to self.
A major question in immunology was how regulatory T cells are developed in the thymus.
In 2002, in Nature Immunology, Liu and his research team revealed the existence of the chemical signal TSLP (thymic stromal lymphopoietin) that activates dendritic cells in the thymus. In 2004, they reported, also in Nature Immunology, that epithelial cells within Hassall's corpuscles express TSLP.
In this study, using human thymus tissue taken during cardiac surgery in children - tissue that otherwise would have been discarded " the researchers isolated different components of thymic cells, and reconstituted them in test tubes. They then conducted numerous experiments over several years, looking at different stages of T cell development and activation of dendritic cells.
They found that Hassall's corpuscles produce chemical signals that direct a specialized group of dendritic cells to turn some of the bad T cells into "good cop" regulatory T cells.
This means that the thymus is providing central tolerance not only through clonal deletion as was previously proposed by the clonal selection theory, but also through clonal conversion, as demonstrated in the current study.
The findings open new avenues in which to further explore the function of regulatory T cells in autoimmune disease and in cancer, the researchers say.
For example, mice experiments show that if regulatory T cells are destroyed, the animals will develop arthritis and other autoimmune diseases. So, if scientists can determine precisely how Hassall's corpuscles and dendritic cells turn T cells into regulatory T cells, it may be possible to "convert" the errant T cells that promote an immune response in tissue into regulatory T cells, thus suppressing such disorders, Liu says.
Similarly, the discovery may help provide clues as to how cancer cells use regulatory T cells to work on their behalf, he says. One of the beneficial roles of regulatory T cells is to suppress the immune system (thus inactivating the damage caused by errant T cells), but "in cancer patients, regulatory T cells become troublemakers, because they suppress any natural reaction the immune system might have mounted to fight the cancer," Liu says.
"It may be that cancer is converting normal T cells into regulatory T cells to protect itself, and once we know the molecular language by which Hassall's corpuscles and dendritic cells induce regulatory T cells, then we might understand how tumor cells also do this," he says.
The study was funded by M. D. Anderson Cancer Foundation and NIH grants to Yong-Jun Liu and his co-authors: first author Norihiko Watanabe, M.D., Ph.D.; Yi-Hong Wang, M.D.; Heung Kyu Lee; Tomoki Ito, M.D.; Yui-His Wang, Ph.D.; and Wei Cao, Ph.D.
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