A major study from researchers at the La Jolla Institute for Allergy and Immunology provides new revelations about the intricate pathways involved in turning on T cells, the body's most important disease-fighting cells, and was published today in the prestigious scientific journal Nature.
The La Jolla Institute team is the first to prove that a certain type of protein, called septins, play a critical role in activating a calcium channel on the surface of the T cell. The channel is the portal through which calcium enters T cells from the blood stream, an action essential for the T cell's survival, activation, and ability to fight disease.
Patrick Hogan and Anjana Rao, Ph.D.s, are senior authors on the paper and Sonia Sharma and Ariel Quintana, Ph.D.s, are co-first authors. Drs. Sharma, Rao and Hogan are former researchers at Harvard Medical School with high-level genetics expertise who joined the La Jolla Institute in 2010. Dr. Quintana conducted advanced microscopy that was a major aspect of the study.
Dr. Hogan describes the discovery as another important step in understanding the overall functioning of T cells – knowledge from which new, more precisely targeted drugs to treat diseases ranging from cancer to viral infections can emerge. "It's like working on an engine, you have to know what all the parts are doing to repair it," he says. "We want to understand the basic machinery inside a T cell. This will enable us to target the specific pressure points to turn up a T cell response against a tumor or virus or to turn it down in the case of autoimmune diseases."
The findings were published in a Nature paper entitled "An siRNA screen for NFAT activation identifies septins as coordinators of store-operated Ca2+ entry."
"We have found that the septin protein is a very strong regulator of the calcium response, which is essential for activating immune cells," says Dr. Sharma, who was recently appointed to a faculty position, and now leads her own independent laboratory at the La Jolla Institute, in addition to serving as scientific director of the newly established RNAi screening center.
Dr. Hogan says the discovery took the research team by surprise. "We knew septins existed in the cellular plasma (surface) membrane, but we didn't know they had anything to do with calcium signaling," he says. Septins are known to build scaffolding to provide structural support during cell division.
This finding builds on Dr. Rao and Dr. Hogan's groundbreaking discovery in 2006 showing that the protein ORAI1 forms the pore of the calcium channel. The channel's entryway had been one of the most sought after mysteries in biomedical science because it is the gateway to T cell functioning and, consequently, to better understanding how the body uses these cells to fight disease.
To the research team's surprise, the septins were forming a ring around the calcium channel. "We aren't sure why, but we theorize that the septins are rearranging the cellular membrane's structure to "corral" the key proteins STIM and ORAI1, and maybe other factors needed for the calcium channel to operate," says Dr. Hogan.
Dr. Sharma adds that, "essentially we believe the septins are choreographing the interaction of these two proteins that are important in instigating the immune response." Without the septins' involvement, T cell activation does not occur.
In the study, the researchers devised a simple visual readout of activity in a main pathway responsible for activation of T cells— the same pathway that is targeted by the immunosuppressive drug cyclosporin A that is used clinically — and looked for impairment of the activity when individual genes were, in effect, deleted. After sorting through the roughly 20,000 human genes, they turned up 887 gene "hits," says Dr. Hogan.
With further experiments, they should be able to classify those hits into genes that affect the calcium channel itself and genes that act later in the pathway. "We are hopeful that one or more of these genes can be used as a clinical target for new drugs to treat transplant rejection and immune diseases, some of the same indications now treated with cyclosporine A," adds Dr. Hogan. He believes that a medication aimed at an early step of calcium entry through the ORAI channel could be more effective and have fewer side effects than cyclosporin A, which targets a later step in the pathway and can cause complications such as kidney disease.
About La Jolla Institute
Founded in 1988, La Jolla Institute for Allergy and Immunology is a nonprofit, independent biomedical research institute focused on improving human health through increased understanding of the immune system. Its scientists carry out research seeking new knowledge leading to the prevention of disease through vaccines and the treatment and cure of infectious diseases, cancer, inflammatory, and autoimmune diseases such as rheumatoid arthritis, type 1 (juvenile) diabetes, Crohn's disease and asthma. La Jolla Institute's research staff includes more than 150 Ph.D.s and M.D.s. To learn more about the Institute's work, visit http://www.lji.org.
Bonnie Ward | EurekAlert!
Innovative genetic tests for children with developmental disorders and epilepsy
11.07.2018 | Christian-Albrechts-Universität zu Kiel
Oxygen loss in the coastal Baltic Sea is “unprecedentedly severe”
05.07.2018 | European Geosciences Union
For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.
To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...
For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.
Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...
Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.
A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...
Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.
"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....
Ultra-short, high-intensity X-ray flashes open the door to the foundations of chemical reactions. Free-electron lasers generate these kinds of pulses, but there is a catch: the pulses vary in duration and energy. An international research team has now presented a solution: Using a ring of 16 detectors and a circularly polarized laser beam, they can determine both factors with attosecond accuracy.
Free-electron lasers (FELs) generate extremely short and intense X-ray flashes. Researchers can use these flashes to resolve structures with diameters on the...
13.07.2018 | Event News
12.07.2018 | Event News
03.07.2018 | Event News
17.07.2018 | Power and Electrical Engineering
17.07.2018 | Life Sciences
16.07.2018 | Physics and Astronomy