Deborah Witherden, a senior staff scientist in Havran lab, was first author of the study titled "The adhesion molecule JAML is a costimulatory receptor for epithelial ? T cell activation" (also with Petra Verdino, Stephanie Rieder, Olivia Garijo, Robyn Mills, Luc Teyton, Wilson, and Havran, all of Scripps Research, and Wolfgang Fischer of the Salk Institute). Verdino, a research associate in the Wilson lab, was first author of the companion publication, "The molecular interaction of CAR and JAML recruits the central cell signal transducer PI3K" (with Witherden, Havran, and Wilson).

A Combined Effort

The Witherden et al. study showed that ? T cells in the skin and intestine require costimulatory signals delivered to the T cells by JAML binding to CAR on damaged keratinocytes. This leads to full activation of the ? T cells and allows them to help heal wounds.

To understand the details of how ? T cells are costimulated, scientists needed to get a three-dimensional view of the molecular interactions that go on between CAR, the ligand on the cell surface of damaged epithelial cells and its receptor JAML on ? T cells. To do this, the scientists turned to a technique called x-ray crystallography, which involves making crystals of ordered arrays of protein and then blasting the frozen crystals with x-ray radiation. The atoms in the protein crystals cause the x-rays to diffract, and the scientists collect and analyze the pattern of diffraction to solve the atomic-level structure of the proteins.

Through this process, the Verdino et al. study determined the exact molecular details of how CAR on keratinocytes and JAML on ? T cells interact. Furthermore, both studies revealed how the CAR-JAML interaction induces signaling events inside the ? T cells that ultimately lead to proliferation and effector functions needed for wound repair.

But how did this basic-science finding translate into an animal model? The Witherden et al. study found that blocking the JAML interaction with CAR in mice led to defects in ? T cell activation and subsequent wound healing. This confirmed that costimulatory signals from JAML are essential for ? T cell responses to wounds.

"The best part of our combined effort," said Verdino, "is that we have put together a comprehensive picture of the role of JAML and CAR for ? T cell function from various perspectives."

The Havran lab's next study, currently under way, will investigate a role for JAML and CAR interactions in activation of ? T cells in humans. Chronic wounds are an increasing clinical problem for patients with diabetes, major burns, and pressure sores. The current studies suggest that JAML and CAR are potential targets for future treatments to stimulate faster wound healing in these patients.

"Identification of an epithelial ? T cell specific activation molecule gives us a unique opportunity to manipulate the T cell response solely in these tissues," Witherden said.

Source: Scripps Research Institute