Foreign entities within the body get chopped into pieces by antigen-presenting cells (APCs), which display the resulting chunks on their surface. These antigens can subsequently be recognized and bound by T cell receptors (TCRs), and the interaction between a T cell and an antigen-bearing APC eventually triggers the onset of an immune response against the antigen.
Inappropriate responses by this system, however, can give rise to disastrous medical consequences, and there is keen interest in developing more sophisticated ways to modulate how T cells react to perceived threats. “Ultimately, we would like to regulate T cell function and activation in order to overcome autoimmune diseases, allergy, or infectious diseases,” explains Takashi Saito, of the RIKEN Center for Allergy and Immunology (RCAI) in Yokohama.
New findings from a team led by Saito and RCAI colleague Tadashi Yokosuka could ultimately prove valuable for such efforts, by revealing insights into the mode of action of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), an inhibitor of TCR signaling1. When T cells associate with APCs, they form what is known as an ‘immunological synapse’, a juncture where numerous proteins assemble into elaborate complexes, such as the central supramolecular activation cluster (cSMAC). By establishing experimental conditions that simulate this cellular interaction, the researchers were able to monitor the dynamic rearrangements that take place at the cSMAC and its environs.
CD28, a T cell protein that promotes TCR signaling, typically assembles at a narrowly defined region of the cSMAC, where it interacts with CD80, a protein expressed on the surface of APCs. Saito, Yokosuka and colleagues determined that CTLA-4 gradually gathers at the immunological synapse and subsequently forms into clusters within the exact same area of the cSMAC as CD28, where it directly competes to bind CD80. “Positive regulation by CD28 and negative regulation by CTLA-4 are induced at the same place in the cell,” says Saito. “Without accumulating at the cSMAC, CTLA-4 cannot inhibit T cell activation.”
In addition to illuminating a mechanism by which T cell responses get fine-tuned, these findings could ultimately yield benefits for patients suffering from a variety of conditions. “Anti-CTLA-4 antibody therapy has been utilized for cancer patients, enhancing tumor immunity by inhibiting regulatory T cells, and CTLA-4-based fusion proteins have been used to block autoimmune diseases such as arthritis,” says Saito. “Our findings will enable us to explore new therapeutic concepts based on the inhibition of the dynamic movement of regulatory molecules such as CTLA-4.”
The corresponding author for this highlight is based at the Laboratory for Cell Signaling, RIKEN Research Center for Allergy and Immunology.
1.Yokosuka, T., Kobayashi, W., Takamatsu, M., Sakata-Sogawa, K., Zeng, H., Hashimoto-Tane, A., Yagita, H., Tokunaga, M. & Saito, T. Spatiotemporal basis of CTLA-4 costimulatory molecule-mediated negative regulation of T Cell activation. Immunity 33, 326–339 (2010).
Novel mechanisms of action discovered for the skin cancer medication Imiquimod
21.10.2016 | Technische Universität München
Second research flight into zero gravity
21.10.2016 | Universität Zürich
Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.
"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...
In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.
A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...
By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.
"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...
COMPAMED has become the leading international marketplace for suppliers of medical manufacturing. The trade fair, which takes place every November and is co-located to MEDICA in Dusseldorf, has been steadily growing over the past years and shows that medical technology remains a rapidly growing market.
In 2016, the joint pavilion by the IVAM Microtechnology Network, the Product Market “High-tech for Medical Devices”, will be located in Hall 8a again and will...
'Ferroelectric' materials can switch between different states of electrical polarization in response to an external electric field. This flexibility means they show promise for many applications, for example in electronic devices and computer memory. Current ferroelectric materials are highly valued for their thermal and chemical stability and rapid electro-mechanical responses, but creating a material that is scalable down to the tiny sizes needed for technologies like silicon-based semiconductors (Si-based CMOS) has proven challenging.
Now, Hiroshi Funakubo and co-workers at the Tokyo Institute of Technology, in collaboration with researchers across Japan, have conducted experiments to...
14.10.2016 | Event News
14.10.2016 | Event News
12.10.2016 | Event News
21.10.2016 | Health and Medicine
21.10.2016 | Information Technology
21.10.2016 | Materials Sciences