Human anti-porcine gammadelta T-cell xenoreactivity is inhibited by human FasL expression on porcine endothelial cells.
BACKGROUND
The role of gammadelta 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 alphabeta T-cell activation occurs. Innate cellular immune response plays a major role in xenograft rejection. We investigated the response of human gammadelta 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 gammadelta 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 gammadelta T-cell clones tested, 38.9% were cytotoxic for porcine endothelial target cells. This cytotoxic response of human gammadelta T-cell clones was significantly inhibited by a monoclonal antibody against human CD3. Incubation of gammadelta 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-alpha monoclonal antibodies. Expression of hFasL on porcine endothelial cells significantly reduced lysis by human gammadelta T cells.


CONCLUSIONS
These results imply that human gammadelta 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.
Rodríguez-Gago
M
M
Unidad de Trasplante, Servicio de Cirugía Experimental, Hospital Universitario Virgen de la Arrixaca, El Palmar, 30120 Murcia, Spain.
de Heredia
A
A
Ramírez
P
P
Parrilla
P
P
Aparicio
P
P
Yélamos
J
J
D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D015478:Antigens, Heterophile / Q000276:immunology*; D002460:Cell Line; D002462:Cell Membrane / Q000276:immunology; D004727:Endothelium / Q000166:cytology / Q000276:immunology*; D053222:Fas Ligand Protein; D053804:Granzymes; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000494:pharmacology* / Q000502:physiology; D016853:Muromonab-CD3 / Q000494:pharmacology; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000187:drug effects / Q000276:immunology*; D012697:Serine Endopeptidases / Q000502:physiology; D013552:Swine
D015478:Antigens, Heterophile; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D007166:Immunosuppressive Agents; D008562:Membrane Glycoproteins; D016853:Muromonab-CD3; D052899:Pore Forming Cytotoxic Proteins; D016692:Receptors, Antigen, T-Cell, gamma-delta; D054353:Perforin; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases