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Sep 1, 2012 (Vol. 32, No. 15)

Wound-Healing Molecular Trigger Found

Process Depends on Skin-Cell Receptor Hooking Up with a Receptor on γδ T Cells

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    The American Diabetes Association estimates that 25.8 million people in the U.S. have diabetes. About 10–15% of these patients are expected to have at least one foot ulcer during their lifetime. New wound-healing therapies represent a critical need for this population. [Cathy Britcliffe/iStock Photo]

    Scientists have uncovered a molecular interaction between two cell types that plays a key role in wound healing and could lead to new therapeutic approaches to speeding the repair of chronic wounds. γδ T cells are dendritic epidermal T cells (DETCs) that provide a first line of defense against tissue damage.

    The cells normally extend multiple dendritic projections that contact neighboring keratinocytes and monitor for signs of damage or disease, and express a specific T cell receptor that recognizes antigens expressed by keratinocytes as a result of trauma.

    Once damage has been detected, the DETCs retract their dendrites, become more rounded in shape, and both DETCs and keratinocytes proliferate and migrate to the site of damage as part of the wound-healing cascade. What hasn’t been determined with any clarity, however, is the pathway of molecular interactions beyond T-cell receptor signaling that regulates the DETC response to keratinocyte damage.

    Using antibodies that block the ability of keratinocytes to activate γδ T cells in vitro, investigators at the Scripps Research Institute working with colleagues at Osaka University in Japan have now found that a keratinocyte surface receptor, plexin B2, binds to the CD100 receptor on T cells.

    “Plexin B2 is very similar to other plexin B family members, including plexin B1, which previously has been shown to bind the CD100 receptor on T cells,” explains Scripps researcher Deborah A. Witherden, Ph.D., who is lead author on the team’s paper published in Immunity. “So we thought that perhaps plexin B2 and CD100 can interact as well.”

    The team then went on to demonstrate that B2-CD100 interaction does indeed appear to play a key role in wound healing. Injured keratinocytes in mice with small skin wounds upregulate expression of plexin B2 soon after the wound occurs, while wounds in mice lacking CD100 on their γδ T cells take longer than normal to heal. “This is very similar to what we see in mice that lack γδ T cells altogether,” Dr. Witherden continues. Notably, deleting CD100 from other types of T cells didn’t affect wound-healing time, suggesting that it is lack of the molecule specifically on γδ T cells that impacts on healing.

    In another set of experiments, the team showed that stimulating CD100 with plexin B2 or with a CD100-binding antibody triggered the dendrite-retracting and shape-changing phenomenon observed in γδ T cells in response to a wound. Subsequent work by the Scripps researchers has also shown that plexin B2-CD100 interaction is needed to activate γδ T cells in the mouse intestinal epithelium, indicating that the same signaling mechanism may be involved in repairing epithelial damage generally, and not just in the skin.

    “This is a major activation pathway for γδ T cells, and it may be a key to treating slow-wound-healing conditions, such as we see in diabetes,” states Scripps Research professor Wendy L. Havran, senior author of the paper. “If deficiencies in this γδ T cell activation pathway are even partly responsible, then we may be able to develop drugs to boost this pathway and treat conditions involving chronic, nonhealing wounds.”


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