For much of the time our T cells—the white blood cells that act as the police of the immune system—are in what immunologists call a "quiescent state," a sort of standby mode. For years, scientists have wondered if quiescence occurred by default or whether T cells need to work at remaining silent.
Now, researchers at The Wistar Institute provide the first direct proof that a protein, called Foxp1, actively maintains this state of quiescence in T cells until the cells are called upon by other parts of the immune system.
Their findings, which appear online through Nature Immunology ahead of print publication, could one day enable researchers to activate T cells to fight diseases such as cancer, which can go undetected or unrecognized by the immune system. In fact, the researchers report that knocking out the Foxp1 protein in mice activates T cells, allowing the cells to work in their policing function.
"T cell quiescence has been a big mystery in immunology with some obvious and profound implications for treating illness by manipulating the immune system," said Hui Hu, Ph.D., senior author of the study and assistant professor in the Immunology Program at The Wistar Institute. "We believe we have provided evidence that quiescence is not just a passive, default state, and we are now beginning to understand the molecular mechanisms by which it happens."
Mature T cells are generated in the thymus, an organ located in front of heart, and then exit into the periphery. There, these T cells are in a "naïve," quiescent state, awaiting orders to act. Activation primarily requires antigen-presenting cell, which offers up an antigen (a particle that the immune system recognizes as "foreign") to the T cell Receptor (TCR). This activated TCR, then, gives the T cell specificity.
Foxp1 is a transcription factor, a protein that binds to DNA and causes the cell to read—or transcribe—specific genes. The Hu laboratory had previously shown that the Foxp1 protein is important for T cell development in the thymus. In order to understand how Foxp1 operates in mature T cells, the researchers used an inducible deletion model system where they could choose to delete the gene's activity after the cells have already matured.
In studying these Foxp1-less T cells, Hu and his colleagues discovered that naive T cells without Foxp1 become activated and proliferate in response to the protein IL-7, without antigen triggers. Hu and his colleagues discovered that Foxp1 represses the expression of the receptor for IL-7, and some other key signaling, in regulating T cell quiescence.
Foxp1, the researchers found, is similar to a related transcription factor, called Foxo1, a well-studied protein with numerous roles in both cancer and aging. In T cells, Foxo1 helps induce the creation of IL-7 receptors, which allows the T cell to receive the IL-7 signal. Foxp1, they found, directly competed with Foxo1's DNA binding spot, thereby limiting the number of IL-7 receptors each T cell has. Such inter-protein competition helps maintain a balanced state within the cell, Hu says.
Among their key findings, Hu believes, is that removing Foxp1 can cause T cells to proliferate without triggering the TCR. "Antigenic specificity is the key characteristic of T cells and our adaptive immunity," Hu. Said. "We never thought a naive T cell could be activated without stimulation through the T cell receptor."
"It came as such a surprise that the deletion of Foxp1, basically the removal of an essential negative regulation, could lead naive T cells to bypass overt antigen recognition and become activated with effector functions," Hu.
According to Hu, his laboratory, in collaboration with fellow laboratories at Wistar, are now investigating the possibility of knocking out Foxp1 to stimulate T cells in the tumor microenvironment.
"Many cancers cause local T cells to become effectively unresponsive or 'quiescent,' thereby allowing tumors to grow unimpeded by the immune system," Hu said. "We suspect that the tumor cells may 'hijack' the cell-intrinsic quiescence mechanism. In addition, many tumor antigens are poorly immunogenic. By manipulating Foxp1 expression, we may bypass the poor tumor antigen stimulation and restore T cell activation within tumors in the hopes that the immune system will clear away cancerous cells."
Funding for this study was provided through grants to Hu from the National Institutes of Health, the American Cancer Society, and The Wistar Institute.
Wistar collaborators include co-first authors postdoctoral fellows Xiaoming Feng, Ph.D., and Haikun Wang, Ph.D., and Hiroshi Takata, Ph.D., and research assistant Timothy J. Day, all of whom are currently members of the Hu lab.
The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the country, Wistar has long held the prestigious Cancer Center designation from the National Cancer Institute. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. The Wistar Institute: Today's Discoveries – Tomorrow's Cures. On the Web at www.wistar.org.
Greg Lester | EurekAlert!
Hunting pathogens at full force
22.03.2017 | Helmholtz-Zentrum für Infektionsforschung
A 155 carat diamond with 92 mm diameter
22.03.2017 | Universität Augsburg
Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.
The results will be published on March 22 in the journal „Astronomy & Astrophysics“.
Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...
Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.
Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...
In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...
20.03.2017 | Event News
14.03.2017 | Event News
07.03.2017 | Event News
22.03.2017 | Materials Sciences
22.03.2017 | Physics and Astronomy
22.03.2017 | Materials Sciences