LA JOLLA, Calif.—A pair of research teams at Scripps Research Institute recently published companion studies that shed light on the underlying mechanisms that activate an immune cell found in skin and other organs. Building on three decades of research about the T cells, called gamma delta cells, the researchers believe their findings could lead to the development of therapies to treat wounds and inflammatory disorders.
For nearly 30 years, scientists at Scripps and elsewhere have been working to understand the role that gamma delta T cells play in the human body. The cells arise early in fetal development in the thymus, and from there migrate to epithelial tissues. The cells are not launched on a "search-and-destroy" mission to heal the skin when it suffers damage, like alpha beta T cells of the immune system do, and they also do not circulate through the bloodstream. Rather, they take up residence in the skin, lung and intestine, where they monitor nearby epithelial cells for damage and disease.
Eight years ago, Wendy Havran, a Scripps research professor, led a study which found that when skin is cut or damaged, wound healing occurs faster with help from gamma delta T cells. But researchers were still unsure of how gamma delta T cells speed wound healing, and Havran and her colleagues set out to close that gap, publishing their results in the Sept. 3 issue of the journal Science.
"These cells play unique and critical roles in recognition of damage or disease in epithelial tissues," says Havran, whose lab has a long-term interest in the development, specificity and function of gamma delta T cells. "Gamma delta T cells are one of the last T-cell populations to be identified. We know a lot about alpha beta T cells and the molecules that are important to their function, but there is not as much known about the molecules involved in the function of gamma delta T cells, most of which need secondary or co-stimulatory signals."
Havran headed up two projects to probe the mechanism of action for gamma delta T cells, hypothesizing that keratinocytes, the major type of epithelial cell in the epidermis, sense damage to the skin and then express an antigen. Havran's study identified a new co-stimulatory molecule for gamma delta T cells that directs the wound healing abilities of these cells; meanwhile, a second team, led by Scripps Research Professor Ian Wilson, focused on the underlying mechanisms of gamma delta T cell co-stimulation, which until now have remained elusive.
According to the studies, the antigens begin mass-producing a growth factor that binds to keratinocytes and other epithelial cells, helping them proliferate and leading to the closure of the wound. The researchers also observed that gamma delta T cells multiply to increase wound-healing response. Specifically, the two papers identified a junctional adhesion molecule (JAML), as a new co-stimulatory receptor for gamma delta T cells that binds to the ligand coxsackie and adenovirus receptor (CAR) expressed on keratinocytes.
In the first study, "The adhesion molecule JAML is a co-stimulatory receptor for epithelial gamma delta T cell activation," the researchers found that blocking the JAML interaction with CAR in mice led to defects in gamma delta T cell activation and subsequent wound healing. This confirmed that co-stimulatory signals from JAML are essential for gamma delta T cell responses to wounds.
The companion study, "The molecular interaction of CAR and JAML recruits the central cell signal transducer PI3K," used X-ray crystallography to determine the exact molecular details of how CAR on keratinocytes and JAML on gamma delta T cells interact.
According to the researchers, their findings hold promise for wound healing and the treatment of inflammatory disorders like asthma, and could even be used to develop therapies for malignant tumors. The team is now working on investigating a role for JAML and CAR interactions in activation of gamma delta T cells in humans.
Havran notes that chronic wounds are an increasing clinical problem for patients with diabetes, major burns and pressure sores.
"Chronic, non-healing wounds are increasingly becoming a clinical problem, particularly for patients with diabetes, or who are elderly or bedridden," she says. "We think there is a lot of interest on the clinical side for developing new targets for wound healing. Our hope with some of these mouse studies is that we will be able to improve some wound healing by increasing the participation of gamma delta T cells through activation of these markers."
The Scripps companion studies were funded by the National Institute of Allergy and Infectious Diseases and National Cancer Institute of the National Institutes of Health, the Skaggs Institute for Chemical Biology at Scripps Research, the Leukemia and Lymphoma Society and an Erwin-Schroedinger Fellowship of the Austrian Science Fund. Facilities and equipment used in the studies were made possible by grants from the National Science Foundation and Vincent J. Coates Foundation, as well as by Stanford Synchrotron Radiation Lightsource and the Advanced Photon Source.
For nearly 30 years, scientists at Scripps and elsewhere have been working to understand the role that gamma delta T cells play in the human body. The cells arise early in fetal development in the thymus, and from there migrate to epithelial tissues. The cells are not launched on a "search-and-destroy" mission to heal the skin when it suffers damage, like alpha beta T cells of the immune system do, and they also do not circulate through the bloodstream. Rather, they take up residence in the skin, lung and intestine, where they monitor nearby epithelial cells for damage and disease.
Eight years ago, Wendy Havran, a Scripps research professor, led a study which found that when skin is cut or damaged, wound healing occurs faster with help from gamma delta T cells. But researchers were still unsure of how gamma delta T cells speed wound healing, and Havran and her colleagues set out to close that gap, publishing their results in the Sept. 3 issue of the journal Science.
"These cells play unique and critical roles in recognition of damage or disease in epithelial tissues," says Havran, whose lab has a long-term interest in the development, specificity and function of gamma delta T cells. "Gamma delta T cells are one of the last T-cell populations to be identified. We know a lot about alpha beta T cells and the molecules that are important to their function, but there is not as much known about the molecules involved in the function of gamma delta T cells, most of which need secondary or co-stimulatory signals."
Havran headed up two projects to probe the mechanism of action for gamma delta T cells, hypothesizing that keratinocytes, the major type of epithelial cell in the epidermis, sense damage to the skin and then express an antigen. Havran's study identified a new co-stimulatory molecule for gamma delta T cells that directs the wound healing abilities of these cells; meanwhile, a second team, led by Scripps Research Professor Ian Wilson, focused on the underlying mechanisms of gamma delta T cell co-stimulation, which until now have remained elusive.
According to the studies, the antigens begin mass-producing a growth factor that binds to keratinocytes and other epithelial cells, helping them proliferate and leading to the closure of the wound. The researchers also observed that gamma delta T cells multiply to increase wound-healing response. Specifically, the two papers identified a junctional adhesion molecule (JAML), as a new co-stimulatory receptor for gamma delta T cells that binds to the ligand coxsackie and adenovirus receptor (CAR) expressed on keratinocytes.
In the first study, "The adhesion molecule JAML is a co-stimulatory receptor for epithelial gamma delta T cell activation," the researchers found that blocking the JAML interaction with CAR in mice led to defects in gamma delta T cell activation and subsequent wound healing. This confirmed that co-stimulatory signals from JAML are essential for gamma delta T cell responses to wounds.
The companion study, "The molecular interaction of CAR and JAML recruits the central cell signal transducer PI3K," used X-ray crystallography to determine the exact molecular details of how CAR on keratinocytes and JAML on gamma delta T cells interact.
According to the researchers, their findings hold promise for wound healing and the treatment of inflammatory disorders like asthma, and could even be used to develop therapies for malignant tumors. The team is now working on investigating a role for JAML and CAR interactions in activation of gamma delta T cells in humans.
Havran notes that chronic wounds are an increasing clinical problem for patients with diabetes, major burns and pressure sores.
"Chronic, non-healing wounds are increasingly becoming a clinical problem, particularly for patients with diabetes, or who are elderly or bedridden," she says. "We think there is a lot of interest on the clinical side for developing new targets for wound healing. Our hope with some of these mouse studies is that we will be able to improve some wound healing by increasing the participation of gamma delta T cells through activation of these markers."
The Scripps companion studies were funded by the National Institute of Allergy and Infectious Diseases and National Cancer Institute of the National Institutes of Health, the Skaggs Institute for Chemical Biology at Scripps Research, the Leukemia and Lymphoma Society and an Erwin-Schroedinger Fellowship of the Austrian Science Fund. Facilities and equipment used in the studies were made possible by grants from the National Science Foundation and Vincent J. Coates Foundation, as well as by Stanford Synchrotron Radiation Lightsource and the Advanced Photon Source.
