Expression of a single gene programs an immune system helper T cell that fuels rapid growth and diversification of antibodies in a cellular structure implicated in autoimmune diseases and development of B cell lymphoma, scientists at The University of Texas M. D. Anderson Cancer Center reported today in Science Express, the advance online publication of the journal Science.
The gene is Bcl6, which the team found plays the crucial role in differentiating a naïve T cell into a T follicular helper cell (Tfh).
"Tfh cells were first noticed in structures called germinal centers found in the lymphoid system - in lymph nodes and the spleen," said senior author Chen Dong, Ph.D., professor in M. D. Anderson's Department of Immunology. Germinal centers are powerful machines that churn out lots of antibodies.
In the adaptive immune system, B cells present an antigen - a distinctive piece of an invading bacterium or virus - to T cells. The bound antigen converts a naïve T cell to a helper T cell that secretes cytokines which help the B cells expand and produce a large volume of antibodies to destroy an intruder.
Tfh cells are concentrated with B cells in germinal centers, where they play a helper T cell's traditional role in B cell proliferation and antibody development.
"In germinal centers, the B cells not only proliferate but they also undergo hypermutation in their immunoglobulin genes so they can produce a diverse class of antibodies," Dong said. "These mutations also allow production of antibodies with stronger affinity for their target antigens."
There are pitfalls to this process. Tfh cells and germinal centers have been implicated in antibody-mediated autoimmune diseases such as lupus and rheumatoid arthritis, Dong noted. In these diseases, the germinal centers are likely producing the wrong type of antibody at great volume.
Genetic hypermutation among B cells in germinal centers creates a hotbed of genomic instability, which gives rise to some types of B cell lymphoma, Dong said.
The scientists set out to understand the role of Bcl6, which is short for B-cell lymphoma 6, a transcription factor previously shown to be selectively expressed in Tfh cells.
Last year, Dong and his colleagues reported in the journal Immunity that cytokines IL-6 and IL-21 drive the differentiation of Tfh cells. However, how these cytokines work had been unclear. In the current study, the team reported that that IL-6 and IL-21 induce expression of Bcl6 in the absence of transforming growth factor beta (TGFß) to drive T cell differentiation into Tfh. "Not only is Bcl6 a transcription factor expressed by Tfh cells, it also has a major function in generating these cells," Dong said.
When TGFß is present with IL-6 and IL-21, T cells differentiate into pro-inflammatory Th17 helper cells.
Another set of experiments showed that Bcl6 expression inhibits a T cell from differentiating into Th17, Th1 or Th2 cells, three other lines of helper cell
Finally, when the Bcl6 gene was knocked out in a mouse model, Tfh was nowhere to be found. "Bcl6 is absolutely required for Tfh generation and it's also important because it blocks other pathways that would lead the T cell into other helper cell types," Dong said.
Solving the molecular programming of Tfh establishes it as the fifth distinct lineage of helper T cell.
Dong and colleagues will continue to characterize Tfh and its relationship to other T helper cells. Dong is co-discoverer of the Th17 cell, which he and colleagues identified as the third T helper cell lineage when conventional wisdom held that there were only two such lines. They also showed that Th17 secretes interleukin-17, which is implicated in both inflammatory and autoimmune diseases.
Co-authors with Dong are first author Roza I. Nurieva, Ph.D., Yeonseok Chung, Ph.D., Gustavo J. Martinez, Xuexian O. Yang, Ph.D., Shinya Tanaka, Ph.D., Tatyana D. Matskevitch, and Yi-Hong Wang, all of M. D. Anderson's Department of Immunology.
The work is supported by research grants from the National Institute of Allergy and Infectious Diseases, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, M. D. Anderson Cancer Center's Center for Targeted Therapy and the Leukemia and Lymphoma Society. Martinez is a Schissler Foundation Fellow in cancer research and a student in The University of Texas Graduate School of Biomedical Sciences, a joint program of M. D. Anderson and the UT Health Science Center at Houston. Chung has a postdoctoral fellowship grant from the Korea Science and Engineering Foundation. Nurieva is recipient of a Scientist Development Grant from the American Heart Association, and Dong is a Leukemia and Lymphoma Society Scholar and a Trust Fellow of M. D. Anderson Cancer Center.
About M. D. Anderson
The University of Texas M. D. Anderson Cancer Center in Houston ranks as one of the world's most respected centers focused on cancer patient care, research, education and prevention. M. D. Anderson is one of only 40 comprehensive cancer centers designated by the National Cancer Institute. For four of the past six years, including 2008, M. D. Anderson has ranked No. 1 in cancer care in "America's Best Hospitals," a survey published annually in U.S. News & World Report.
Scott Merville | EurekAlert!
Researchers identify potentially druggable mutant p53 proteins that promote cancer growth
09.12.2016 | Cold Spring Harbor Laboratory
Plant-based substance boosts eyelash growth
09.12.2016 | Fraunhofer-Institut für Angewandte Polymerforschung IAP
Physicists of the University of Würzburg have made an astonishing discovery in a specific type of topological insulators. The effect is due to the structure of the materials used. The researchers have now published their work in the journal Science.
Topological insulators are currently the hot topic in physics according to the newspaper Neue Zürcher Zeitung. Only a few weeks ago, their importance was...
In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.
Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...
Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
09.12.2016 | Life Sciences
09.12.2016 | Ecology, The Environment and Conservation
09.12.2016 | Health and Medicine