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Researchers Identify Molecular Switch Enabling Immune Cells to Better Fight Disease

Sunday, January 20, 2013

CD4 Helper T Cell
 
Medicine
A research effort 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.
Researchers 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.

"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."

Normally, CD4 helper T cells, 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. Studies conducted earlier showed 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.

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.

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.  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 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.

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."

Dr. Cheroutre said she also 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.

According to Cheroutre, "Rather than figuring out how to treat disease, I’d like to understand how to prevent it. It would be a wonderful thing if we could stop terrible diseases before they have a chance to do any damage."

SOURCE  La Jolla Institute

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