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!
Progress in Super-Resolution Microscopy
17.12.2018 | Julius-Maximilians-Universität Würzburg
Communication between neural networks
17.12.2018 | Albert-Ludwigs-Universität Freiburg im Breisgau
Researchers from the University of Basel have reported a new method that allows the physical state of just a few atoms or molecules within a network to be controlled. It is based on the spontaneous self-organization of molecules into extensive networks with pores about one nanometer in size. In the journal ‘small’, the physicists reported on their investigations, which could be of particular importance for the development of new storage devices.
Around the world, researchers are attempting to shrink data storage devices to achieve as large a storage capacity in as small a space as possible. In almost...
The more objects we make "smart," from watches to entire buildings, the greater the need for these devices to store and retrieve massive amounts of data quickly without consuming too much power.
Millions of new memory cells could be part of a computer chip and provide that speed and energy savings, thanks to the discovery of a previously unobserved...
What if, instead of turning up the thermostat, you could warm up with high-tech, flexible patches sewn into your clothes - while significantly reducing your...
A widely used diabetes medication combined with an antihypertensive drug specifically inhibits tumor growth – this was discovered by researchers from the University of Basel’s Biozentrum two years ago. In a follow-up study, recently published in “Cell Reports”, the scientists report that this drug cocktail induces cancer cell death by switching off their energy supply.
The widely used anti-diabetes drug metformin not only reduces blood sugar but also has an anti-cancer effect. However, the metformin dose commonly used in the...
A research team from the University of Zurich has developed a new drone that can retract its propeller arms in flight and make itself small to fit through narrow gaps and holes. This is particularly useful when searching for victims of natural disasters.
Inspecting a damaged building after an earthquake or during a fire is exactly the kind of job that human rescuers would like drones to do for them. A flying...
12.12.2018 | Event News
10.12.2018 | Event News
06.12.2018 | Event News
17.12.2018 | Studies and Analyses
17.12.2018 | Life Sciences
17.12.2018 | Power and Electrical Engineering