Old Mystery Solved, Revealing Origin Of Regulatory T Cells That 'Police' And Protect The Body

Reporting in the Aug. 25 issue of Nature, researchers at TheUniversity of Texas M. D. Anderson Cancer Center found that Hassall'scorpuscles produce chemical signals that instruct dendritic cells inthe thymus to induce development of these regulatory T cells - thecritically important immune system cells that patrol the body lookingfor "bad' T cells that can produce autoimmune disease.

"These mysterious little structures in the thymus areresponsible for producing the T cell policemen that our bodies dependso 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 avery smart system that evolved during evolution to efficiently keep theimmune system in check."

The thymus functions like a school to educate immature immunesystem "T" (for thymus) cells. T cells are white blood cells that playvital roles in the immune system, including the identification ofspecific foreign "antigens" in the body (toxins, bacteria, viruses andother invading cells) and the activation and deactivation of otherimmune cells.

A chief function of the thymus is the selection of the T cellrepertoire the immune system uses to combat infections - a processknown as "clonal selection theory" that earned the researchers whodiscovered it a Nobel Prize in 1960. This involves the "positiveselection" of T cells that are non self-reactive and the elimination,through "negative selection," of T cells that are self-reactive orautoreactive. If allowed outside of the thymus gland, theseautoreactive T cells would produce a harmful immune response againstthe body's own tissues, so the immune system flags "dendritic" cellswithin the thymus to eliminate these bad cells. T cells that pass bothlevels of selection are then released into the bloodstream to performvital immune functions.

"It was believed that the only way to induce what is known ascentral tolerance was by deleting harmful T cells during development,"says Liu.

But scientists now know that not all the "bad" T cells aredestroyed through negative selection. Some autoreactive T cells escapethe thymic censorship process and are released into the circulation.For that reason, researchers searched for additional mechanisms thatexist in the blood and lymph system outside of the thymus to take careof these bad actors - which led to the discovery of regulatory T cells.These special T cells act like policemen to scour out dangerous T cellsand suppress activation of the immune system, and thus maintaintolerance 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 theexistence 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'scorpuscles express TSLP.

In this study, using human thymus tissue taken during cardiacsurgery in children - tissue that otherwise would have been discarded "the researchers isolated different components of thymic cells, andreconstituted them in test tubes. They then conducted numerousexperiments over several years, looking at different stages of T celldevelopment and activation of dendritic cells.

They found that Hassall's corpuscles produce chemical signals thatdirect a specialized group of dendritic cells to turn some of the bad Tcells into "good cop" regulatory T cells.

This means that the thymus is providing central tolerance not onlythrough clonal deletion as was previously proposed by the clonalselection theory, but also through clonal conversion, as demonstratedin the current study.

The findings open new avenues in which to further explore the functionof regulatory T cells in autoimmune disease and in cancer, theresearchers say.

For example, mice experiments show that if regulatory T cellsare destroyed, the animals will develop arthritis and other autoimmunediseases. So, if scientists can determine precisely how Hassall'scorpuscles and dendritic cells turn T cells into regulatory T cells, itmay be possible to "convert" the errant T cells that promote an immuneresponse in tissue into regulatory T cells, thus suppressing suchdisorders, Liu says.

Similarly, the discovery may help provide clues as to howcancer cells use regulatory T cells to work on their behalf, he says.One of the beneficial roles of regulatory T cells is to suppress theimmune 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 havemounted to fight the cancer," Liu says.

"It may be that cancer is converting normal T cells into regulatory Tcells to protect itself, and once we know the molecular language bywhich Hassall's corpuscles and dendritic cells induce regulatory Tcells, then we might understand how tumor cells also do this," he says.

The study was funded by M. D. Anderson Cancer Foundation and NIHgrants to Yong-Jun Liu and his co-authors: first author NorihikoWatanabe, 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.