"This finding gives us insights into immune regulation that could be very helpful in a range of medical applications, from viral vaccines to treatments for autoimmune diseases," said Changchun Xiao, assistant professor in TSRI's Department of Immunology and Microbial Science and senior investigator for the study, which appears in the June 30, 2013 issue of Nature Immunology.
Unraveling a Crucial Process
The finding concerns a key interaction between T cells and B cells, the allied lymphocyte armies that make up most of the adaptive immune system of mammals. B cells, which produce antibodies, usually lie in wait for pathogens in special zones called follicles within lymph nodes and the spleen. But to start proliferating normally and pumping out antibodies to fight an infection, these B cells have to be assisted, in effect, by T cells known as "follicular helper" T cells (TFH cells). "The TFH cells have to migrate into the B cell follicles and physically contact the B cells in order to provide help to them," said Xiao. "However, the molecular pathways that control TFH cell differentiation and migration have not been well understood."
In 2009, other researchers proposed that this crucial process requires the suppression of the miR-17~92 family of RNA molecules. These are among the thousands of short RNA molecules (often known as micro-RNAs, miRs, or miRNAs) that are made by mammalian cells and are meant to do their jobs while in RNA form. Typically an miRNA works inside the cell as a basic regulator or "dimmer switch" for the activity of tens to hundreds of genes—it binds to transcripts of those genes and slows down their translation into proteins.
Xiao, who had been studying the miR-17~92 family since 2005, decided to examine their role in TFH differentiation. His team began by measuring the levels of these miRNAs in young, "naïve" T cells and in the TFH cells to which these T cells gave birth after exposure to foreign antigens.
To the researchers' surprise, the miR-17~92s showed the opposite pattern of expression than expected: their levels jumped as the naïve T cells began differentiating into TFH cells, but fell back by the time the process was finished. The finding suggested that, far from acting as a brake on TFH differentiation, miR-17~92s work as enablers of the process.
To confirm their suspicion, team members developed mutant mouse lines in which some or all of the miR-17~92 miRNAs were knocked out of T cells. These miR-17~92-deficient T cells turned out to be much less able to differentiate into TFH cells. As a result, the follicle-dwelling B cells that depend on TFH assistance also lost much of their ability to respond to an immune challenge. "These mutant mice showed a deficient antibody response to a standard immune-provoking protein," said Seung Goo Kang, a postdoctoral research associate in the Xiao laboratory who was the leading author of the study.
Collaborating TSRI scientists led by John Teijaro, a senior research associate in the laboratory of Michael B. A. Oldstone, professor in the Department of Immunology and Microbial Science, showed further that these transgenic mice—unlike ordinary lab mice—could not clear a chronic virus infection that is used as a standard challenge in immunological experiments.
By contrast, when the team raised transgenic mice whose T cells produced four to six times the normal amount of miR-17~92s, these T cells differentiated into TFH cells spontaneously—that is, without an immune-stimulating inoculation.
These mice developed antibody responses to their own tissues, and died young, with swollen spleen and lymph nodes. "The accumulation of autoantibodies is also seen in lupus and other autoimmune diseases in humans," said Wen-Hsien Liu, another postdoctoral research associate in the Xiao laboratory and a co-first author of the paper.
Liu and Kang were able to track down a key target gene of miR-17~92s, which the miRNAs suppress to enable TFH cell differentiation. The targeted gene codes for Phlpp2, a recently discovered signaling inhibitor. "Lowering Phlpp2 protein levels in our miR-17~92-knockout T cells restored much of their ability to become TFH cells," Kang said.
"Phlpp2 is one important target, but we believe there are others too, and we are now looking for those," Xiao said. He and his colleagues also plan to investigate methods for manipulating miR-17~92s and their TFH cell-related pathways, in order to boost antibody responses – to vaccines for example—or alternatively to lower autoantibody productions in people with autoimmune diseases.
The study, "miR-17~92 family microRNAs are critical regulators of T follicular helper cell differentiation," was a collaboration that also involved the laboratory of Hai Qi at Tsinghua University in Beijing and the laboratory of Eric Verdin at the Gladstone Institute of Virology and Immunology at the University of California, San Francisco. A co-first author of the study was Peiwen Lu of the Qi laboratory; other co-authors were Hyung W. Lim of the Verdin laboratory, Daniel Fremgen of the Oldstone laboratory and Hyun Yong Jin and Jovan Shepherd of the Xiao laboratory.
The study was funded by the PEW Charitable Trusts, the Cancer Research Institute, the Lupus Research Institute, the American Heart Association (grant 11POST7430106 ), the National Institutes of Health (R01AI019484 and R01AI087634) and the National Natural Science Foundation of China (81161120405).
Mika Ono | EurekAlert!
Programming cells with computer-like logic
27.07.2017 | Wyss Institute for Biologically Inspired Engineering at Harvard
Identified the component that allows a lethal bacteria to spread resistance to antibiotics
27.07.2017 | Institute for Research in Biomedicine (IRB Barcelona)
Physicists working with researcher Oriol Romero-Isart devised a new simple scheme to theoretically generate arbitrarily short and focused electromagnetic fields. This new tool could be used for precise sensing and in microscopy.
Microwaves, heat radiation, light and X-radiation are examples for electromagnetic waves. Many applications require to focus the electromagnetic fields to...
Strong light-matter coupling in these semiconducting tubes may hold the key to electrically pumped lasers
Light-matter quasi-particles can be generated electrically in semiconducting carbon nanotubes. Material scientists and physicists from Heidelberg University...
Fraunhofer IPA has developed a proximity sensor made from silicone and carbon nanotubes (CNT) which detects objects and determines their position. The materials and printing process used mean that the sensor is extremely flexible, economical and can be used for large surfaces. Industry and research partners can use and further develop this innovation straight away.
At first glance, the proximity sensor appears to be nothing special: a thin, elastic layer of silicone onto which black square surfaces are printed, but these...
3-D shape acquisition using water displacement as the shape sensor for the reconstruction of complex objects
A global team of computer scientists and engineers have developed an innovative technique that more completely reconstructs challenging 3D objects. An ancient...
Physicists have developed a new technique that uses electrical voltages to control the electron spin on a chip. The newly-developed method provides protection from spin decay, meaning that the contained information can be maintained and transmitted over comparatively large distances, as has been demonstrated by a team from the University of Basel’s Department of Physics and the Swiss Nanoscience Institute. The results have been published in Physical Review X.
For several years, researchers have been trying to use the spin of an electron to store and transmit information. The spin of each electron is always coupled...
26.07.2017 | Event News
21.07.2017 | Event News
19.07.2017 | Event News
27.07.2017 | Life Sciences
27.07.2017 | Life Sciences
27.07.2017 | Health and Medicine