TGF-beta regulates immune system balance by driving generation of regulatory T cells
Without regulatory T cells (Treg cells), you’d likely die from out-of-control inflammation. Treg cells prevent your immune system from attacking your own tissues. Wanjun Chen, M.D., Chief of NIDCR’s Mucosal Immunology Section in the Oral and Pharyngeal Cancer Branch, and National Institutes of Health colleagues reported in a recent issue of the Proceedings of the National Academy of Sciences that they’ve figured out that the indispensable ingredient for making Treg cells in the thymus is TGF-beta (transforming growth factor-beta).
Disease results if immune system lacks yin-yang balance
You’ve heard before that you never want too much or too little of anything. If one of the elements in the immune system is out of balance, disease results. Chen uses the Chinese yin and yang concept to describe the immune system. Just as yin and yang, black and white, night and day, and moon and sun are complementary forces that are connected and dependent, the immune system maintains a balance between tolerance for self tissues (because of Treg cells) and immunity from foreign invaders (because of other immune cells known as effector T cells). Without sufficient Treg cells, you’ll have autoimmune diseases and inflammation, and without sufficient effector T cells, you won’t be protected against pathogens and other unwanted intruders.
TGF-beta drives the generation of Treg cells
Immunology is a relatively young science, and immunologists devise models to explain the behavior of cells and molecules within the immune system. Little by little, experiments are conducted, and models are argued and proved, modified, or discarded. For Treg cell biology, the models have been incomplete. One immunological mystery that needed to be solved was how Treg cells in the thymus are generated from progenitor T cells derived in the bone marrow. Another question was why newborns don’t have thymic Treg cells until the third day after birth.
To solve these and other mysteries, many groups are investigating how the Treg cell develops. “It’s a very prominent area of research right now,” said the paper’s first author, NIH Visiting Fellow Joanne Konkel, who has worked in Chen’s lab for a few years.
Through a series of experiments with lab mice, Chen, Konkel, and colleagues found that the thymus doesn’t have very much TGF-beta until the third day after birth, and as soon as the TGF-beta level is high enough, the Treg cell factory gears up.
According to Chen, many in the field have overlooked the normal process of cell self-destruction (apoptosis) in the model of how Treg cells are generated in the thymus. Chen and colleagues demonstrated that apoptotic cells lead to TGF-beta production, which in turn leads to Treg cell development in the thymus. Without TGF-beta, Treg cells are not generated in the thymus.
“We did not follow the dogma,” said Chen. Instead, his team’s experiments challenged the existing models of immunology. It took about a decade for the comprehensive experiments to arrive at the answer to the questions about how Treg cells develop in the thymus.
Konkel said, “This is a basic immunology question that we’ve managed to provide some kind of insight into.” Because of the new findings at NIH, immunology has a better model to explain Treg cell development. Before Konkel leaves NIH in June to establish her own research lab, she hopes her current experiments will advance knowledge of Treg cell function in the way that her studies have advanced understanding of Treg cell development. Such descriptions of the pathways and molecular players involved in Treg cell development and function might someday identify molecular targets for developing therapies for people with autoimmune diseases, such as Sjögren’s syndrome and multiple sclerosis, and for people with oral cancer or other types of cancer.
NIDCR research provides answers to fundamental questions in immunology
It’s not the first time that Chen’s research at NIDCR has answered a fundamental question in immunology. A previous journal article by Chen, which was published in 2003 in JEM (Journal of Experimental Medicine), identified TGF-beta as the critical factor in the development of peripheral Treg cells. The 2003 TGF-beta article in JEM has been cited thousands of times, and only two other JEM articles have been cited more times than Chen’s paper. Just as the 2003 JEM article established TGF-beta’s role in peripheral Treg cell development, the PNAS article gives TGF-beta a central role in thymic Treg cell generation.
Konkel JE, Jin W, Abbatiello B, Grainger JR, Chen W. Thymocyte apoptosis drives the intrathymic generation of regulatory T cells. Proc Natl Acad Sci U S A. 2014 Jan 28;111(4):E465-73.