Human anti-porcine gamma delta T-cell xenoreactivity is inhibited by humanFasL expression on porcine endothelial cells

Background. The role of gamma delta T cells during an immune response is st ill elusive and has been proposed to play a first line of defense along wit h other cells of the innate immune system, such as macrophages and natural killer cells, before alpha beta T-cell activation occurs. Innate cellular i mmune response plays a major role in xenograft rejection. We investigated t he response of human gamma delta T cells to unmodified and human FasL (hFas L)-expressing xenogenic porcine endothelial cells. Methods. A Cr-51 release assay was used to study the xenoreactivity of huma n gamma delta T-cell clones against porcine endothelial cells. Stable trans fectants of porcine endothelial cells expressing hFasL were established and analyzed for their effectiveness in controlling this response. Results. Of the gamma delta T-cell clones tested, 38.9% were cytotoxic for porcine endothelial target cells. This cytotoxic response of human gamma de lta T-cell clones was significantly inhibited by a monoclonal antibody agai nst human CD3. Incubation of gamma delta T-cell clones with con-canamycin A , an inhibitor of the perforin/granzyme B pathway, caused inhibition of lys is of porcine endothelial. cells. Inhibition was not observed upon incubati on with either anti-FasL or anti-tumor necrosis factor-a monoclonal antibod ies. Expression of hFasL on porcine endothelial cells significantly reduced lysis by human gamma delta T cells. Conclusion. These results imply that human gamma delta T cells may represen t an important obstacle to xenotransplantation. Specific strategies targete d at this subset of T cells could be important in controlling innate cellul ar response to xenografts and facilitate graft survival.