A research team led by the La Jolla Institute for Allergy & Immunology has discovered the mechanism that enables CD4 helper T cells to assume the more aggressive role of killer T cells in mounting an immune attack against viruses, cancerous tumors and other damaged or infected cells.
The finding, made in collaboration with researchers from the RIKEN Institute in Japan, could enable the development of more potent drugs for AIDS, cancer and many other diseases based on using this mechanism to trigger larger armies of killer T cells against infected or damaged cells.
CD4 helper T cells, which normally assist other cells of the immune system during an infection, and CD8 killer T cells, which directly attack and eliminate infected cells, are two of the body's most important immune cells for defending against diseases. Earlier research studies have shown that helper T cells can become killer cells in some instances. However, the specific mechanism of action that allowed this to occur was not known until now.
"We have identified the molecular switch that enables CD4 T cells to override their programming as helper cells and transform into cytolytic (killer) cells," said La Jolla Institute scientist and study co-leader Hilde Cheroutre, Ph.D. "Our team also showed that these transformed helper T cells represent a separate and distinct population of cells. They are not a subset of TH-1 helper cells as previously thought."
Jay A. Berzofsky, M.D., Ph.D., chief of the Vaccine Branch at the National Cancer Institute's Center for Cancer Research, called the finding "a major advance" that provides new understanding about the cell's lineage and basic mechanisms. Dr. Berzofsky was among the researchers whose work in the 1980s first demonstrated that helper cells could convert to killer cells. "Understanding how these cells derive and what causes them to switch from helper T cells to cytolytic T cells is an important step to learning how to manipulate them in disease," he said, noting it could lead to novel approaches "either to turn these cells off in autoimmune disease or turn them on in infectious diseases."
He added that the finding could also have important implications in cancer. "We need all of the cytolytic machinery that we can get to try to destroy cancers," he said. "If we can learn to turn them on, I think it's reasonable to believe that these cytolytic T cells can play an important role in controlling cancer."
The findings were published today in Nature Immunology in a paper entitled "Transcriptional reprogramming of mature CD4 helper T cells generates distinct MHC class II-restricted cytotoxic T lymphocytes." Dr. Cheroutre is co-senior author on the study together with Dr. Ichiro Taniuchi of the RIKEN Research Center for Allergy and Immunology in Yokohama, Kanagawa, Japan. First authors on the paper are: Mohammad Mushtaq Husain, Ph.D., of the La Jolla Institute; Daniel Mucida, Ph.D., formerly of the La Jolla Institute, now at Rockefeller University; Femke van Wijk, Ph.D., formerly of the La Jolla Institute, now at the University Medical Center Utrecht, The Netherlands, and Sawako Muroi, of the RIKEN Institute.
Mitchell Kronenberg, Ph.D., La Jolla Institute president & chief scientific officer, said the study reflects the very successful collaboration between the La Jolla Institute and RIKEN in Japan, which have joined efforts on a number of projects over the years.
In the study, the researchers found that a certain transcription factor, which are molecules in the cell nucleus that control the activity of cells, continually suppresses the killer T cell lineage in helper T cells. Using mice, the team showed that turning off this transcription factor (ThPOK) enabled the helper cells in the body's peripheral areas, like the blood, spleen and the intestine, to override their original programming and to become killer T cells. "While our work focused on the intestines, we found that helper T cells in all tissues of the body have the potential to become killer cells in response to recognition of viral, tumor or other antigens in the context of cytokines such as IL-15," said Dr. Cheroutre.
Jonathan Braun, M.D., chair of the Department of Pathology and Laboratory Medicine at UCLA's David Geffen School of Medicine, praised the study as laying the groundwork for using T helper cells in a much more aggressive manner. "Helper T cells are mainly understood for their role in regulating other immune cells," he said. "This work reveals how they themselves can be triggered to become the action cells in the immune response. This opens new possibilities for how to manipulate them therapeutically in disease."
Dr. Cheroutre said the transformation of CD 4 helper T cells into killer cells already occurs in the body naturally. "Our finding could help to explain a number of occurrences that we haven't really understood up to this point, such as why some people can be chronically infected with HIV without developing AIDS." In these instances, Dr. Cheroutre is convinced that CD4 helper T cells must be taking over the role of killer cells after the CD8 T cells become exhausted. "It's like the helper cells can come in as reinforcements to keep the virus under control. If we can develop ways to artificially trigger that process, we may be able to significantly help people with HIV and other chronic infections."
While scientists would want to trigger a larger army of virus-specific killer cells in the case of infections, the opposite would be true in inflammation-fueled autoimmune diseases, like rheumatoid arthritis or multiple sclerosis, said Dr. Cheroutre. "The CD4 T cells are the bad wolves in inflammatory diseases because they often trigger more pro-inflammatory cells which worsen these conditions," she said. "With this knowledge, we may be able to prevent that by coaxing the CD4 killer cells to become regulatory cells instead, which is another one of their potential functions. In regulatory mode, the CD4 T cells suppress the immune system. This suppression reduces inflammatory cells, which is what we want to do in autoimmune diseases."
However in cancer, the CD4 T cell's regulatory function becomes problematic because they inhibit the killer T cells from destroying cancerous cells. This is because of their built-in mechanism to keep T cells from attacking the body's own cells, said Dr. Cheroutre. "Cancer cells develop from our own cells and only look a little different from healthy cells," she explained. "The killer T cells can sense that they are different and decide to eliminate them. However, the CD4 regulatory T cells frequently suppress the killer T cells and prevent them from destroying the cancerous cells. This is often how cancer cells can escape the immune system's normal action of stamping out bad cells."
Dr. Cheroutre said she believes it may be possible, using the newly discovered mechanism, to turn the CD4 regulatory T cells into killer cells that would aid, rather than block, the immune system's attack on cancerous cells.
About La Jolla Institute
Founded in 1988, the La Jolla Institute for Allergy & Immunology is a biomedical research nonprofit 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 www.liai.org.
Bonnie Ward | EurekAlert!
Further reports about: > Aids > Allergy > CD4+ T cells > CD4-Rezeptor > Cancer > HIV > Immunology > Nature Immunology > RIKEN > T cells > T lymphocyte > autoimmune disease > cancerous cells > cancerous tumor > chronic infection > healthy cell > immune cell > immune system > infected cells > infectious disease > inflammatory cells > inflammatory disease > killer T cells > rheumatoid arthritis > transcription factor
World’s Largest Study on Allergic Rhinitis Reveals new Risk Genes
17.07.2018 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt
Plant mothers talk to their embryos via the hormone auxin
17.07.2018 | Institute of Science and Technology Austria
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 | Information Technology
17.07.2018 | Materials Sciences
17.07.2018 | Power and Electrical Engineering