HUMAN ANTI-PORCINE ???? T-CELL XENOREACTIVITY IS INHIBITED BY HUMAN FasL EXPRESSION ON PORCINE ENDOTHELIAL CELLS1

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Abstract
Background. The role of γδ T cells during an immune response is still elusive and has been proposed to play a first line of defense along with other cells of the innate immune system, such as macrophages and natural killer cells, before αβ T-cell activation occurs. Innate cellular immune response plays a major role in xenograft rejection. We investigated the response of human γδ T cells to unmodified and human FasL (hFasL)-expressing xenogenic porcine endothelial cells. Methods. A 51Cr release assay was used to study the xenoreactivity of human γδ T-cell clones against porcine endothelial cells. Stable transfectants of porcine endothelial cells expressing hFasL were established and analyzed for their effectiveness in controlling this response. Results. Of the γδ T-cell clones tested, 38.9% were cytotoxic for porcine endothelial target cells. This cytotoxic response of human γδ T-cell clones was significantly inhibited by a monoclonal antibody against human CD3. Incubation of γδ T-cell clones with concanamycin A, an inhibitor of the perforin/granzyme B pathway, caused inhibition of lysis of porcine endothelial cells. Inhibition was not observed upon incubation with either anti-FasL or anti-tumor necrosis factor-α monoclonal antibodies. Expression of hFasL on porcine endothelial cells significantly reduced lysis by human γδ T cells. Conclusion. These results imply that human γδ T cells may represent an important obstacle to xenotransplantation. Specific strategies targeted at this subset of T cells could be important in controlling innate cellular response to xenografts and facilitate graft survival.