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    Scientists offer new details of the immune system’s quest for balance

    Dario Vignali

    From the laboratory of Dario Vignali, PhD, Immunology, comes new evidence that like unruly children who secretly welcome the intervention of a stern teacher, certain aggressive lymphocytes invite suppression by other immune cells.

    Writing in the May 15 edition of The Journal of Immunology, the St. Jude investigators reported new details of the complex dance that helps maintain immune balance. The work highlights the role that a small protein known as interleukin 35 (IL-35) plays in regulating suppression within the immune system. IL-35 is a novel member of a larger family of signaling molecules, known as cytokines or in the immune system as interleukins, which cells rely on to communicate and to influence how cells behave.

    IL-35 was identified earlier in Vignali’s laboratory and remains one of just three out of more than 50 cytokines that dampen rather than fuel the immune response. The new findings build on the laboratory’s earlier work that suggested IL-35 was central to the regulatory function of lymphocytes known as regulatory T cells. Regulatory T cells are the immune cells crucial for maintaining the immune system’s equilibrium. Effector T cells drive inflammation and the immune response. Regulatory T cells help keep them from running amok.

    A long-standing tenant of modern immunology was that regulatory T cells must contact effector T cells to mediate their suppression. This assumption minimized the importance of soluble inhibitory cytokines. The new study from the Vignali lab challenges this view. The findings show that direct contact between regulatory and effector T cells is required to maximally activate regulatory T cells but not to mediate their suppressive activity. While the new research shows direct contact between the two cell types is important to potentiate suppression, Vignali said the findings point to cytokines, particularly IL-35, as the primary mechanism of regulatory action. Vignali is the paper’s senior author.

    These findings overturn the established tenet that emphasized direct contact between the cells as central to regulatory T cell action. This study shows that when regulatory T cells are appropriately stimulated they do not require direct contact with effector T cells to dampen effector T cell activity.

    The findings also provide insight into how regulatory T cells exert control despite being vastly outnumbered by effector T cells, said Lauren Collison, PhD, a postdoctoral fellow in Vignali’s laboratory and the paper’s lead author. The researchers speculated cytokines might allow a lone regulatory T cell to suppress activity of several effector T cells. The cytokines might also allow for creation of microenvironments within the body, dampening the inflammatory response in particular parts of the body such as lymph nodes.

    The work also suggests new treatment and prevention targets for a variety of human diseases, including arthritis, allergies and the inflammatory response following an infection. Vignali said research is underway to uncover the molecular interaction at the heart of the effector and regulatory T cell interaction.

    The findings also reconcile earlier results about the role of another cytokine, interleukin 10 (IL-10).

    This work stems from an observation in a 2007 paper describing IL-35 and its function. In it, the St. Jude investigators noted that when effector and regulatory T cells shared a laboratory dish, regulatory T cells increased production of messenger RNA, a decoded form of the two proteins that make up IL-35. Those proteins are Ebi3 and II12a. The observation suggested effector T cells were driving production of IL-35 by regulatory T cells.

    “We felt regulatory T cells were not just simply on or off, but like many other immune cells, received cues from the environment that regulates their activity,” Vignali explained.

    For this study, Collison used a specialized piece of laboratory equipment known as a Transwell plate in a novel way. The small plastic plates are dotted with wells about the size of an eraser on a No. 2 pencil. Collison used a permeable membrane to divide the wells. The membrane prevented direct contact between cells on either side, but allowed IL-35, IL-10 and other molecules to flow between the two chambers.

    In this case, researchers charted the response of activated effector T and regulatory T cells in the Transwell plate separated by a permeable membrane. Plastic beads coated with antibodies were added to each side to spark the immune response.

    Although the cells were not in direct contact, after 72 hours, regulatory T cell suppression of effector T cells jumped 40 percent when regulatory T cell activity was boosted by direct contact with a separate T cell population. These observations suggested that this suppression was mediated by a soluble factor. When the same experiments were done using regulatory T cells that could not make either IL-35 or IL-10, no increased suppression occurred. The researchers noted the findings raise the possibility that regulatory T cells need IL-10 and IL-35 to maximize effector T cell suppression.

    “The cells are talking to each other in an interactive way,” Vignali said. IL-35 and IL-10 drive the conversation, which in some cases occurs across great distances within the body.

    The paper’s other authors are Meenu Pillai, PhD, and Vandana Chaturvedi, PhD, both of Immunology.

    The work was supported in part by grants from the National Institutes of Health, the National Cancer Institute, a St. Jude Gephardt postdoctoral fellowship, an Individual National Research Service Award and ALSAC.

    July 2009