Cross-species costimulation: relative contributions of CD80, CD86, and CD40.
BACKGROUND
The response of human CD4+ T cells against porcine cells is of comparable magnitude to that induced by human leukocyte antigen-mismatched allogeneic cells. This reflects productive interactions between key costimulatory molecules across the species barrier. Inhibition of these molecular interactions will be crucial in overcoming CD4+ T-cell-mediated rejection of xenografts. We have performed a detailed investigation to determine the expression profiles and relative contributions of the three key costimulatory molecules in the porcine-human xenogeneic response. Whereas only porcine CD86 is constitutively expressed on resting endothelial cells, both CD40 and CD80 are rapidly expressed after activation. All three costimulatory molecules are expressed by professional antigen-presenting cells.


METHODS
We have isolated full-length cDNA clones for human and porcine CD80, CD86, and CD40. Human fibroblast cell lines (M1) coexpressing DR1 were transfected with these cDNAs and used in mixed lymphocyte reactions and flow cytometric studies in vitro.


RESULTS
These data provide the first characterization of the expression profile and functional role of porcine CD80. Functional assays demonstrate that pCD40, pCD80, and pCD86 are independently capable of costimulating human CD4+ T cells, albeit with differing kinetics. Proliferative responses were of comparable magnitude to those obtained when costimulation was provided by human CD40, CD80, and CD86.


CONCLUSIONS
These data have implications for therapy targeting the direct pathway of xenorecognition; costimulatory molecule blockade must be directed against both the B7/CD28 and CD40/CD40L pathways.
Rogers
Nicola J
NJ
Department of Immunology, Imperial College of Science, Technology and Medicine, Hammersmith Campus, London.
Jackson
Ian M
IM
Jordan
William J
WJ
Hawadle
Muhamed A
MA
Dorling
Anthony
A
Lechler
Robert I
RI
D000818:Animals; D015703:Antigens, CD / Q000235:genetics*; D018122:B7-1 Antigen / Q000235:genetics*; D051940:B7-2 Antigen; D001483:Base Sequence; D019013:CD40 Antigens / Q000235:genetics*; D017931:DNA Primers; D018076:DNA, Complementary; D005347:Fibroblasts / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000235:genetics*; D008969:Molecular Sequence Data; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013045:Species Specificity; D013552:Swine; D013601:T-Lymphocytes / Q000276:immunology*; D013997:Time Factors; D014183:Transplantation, Heterologous / Q000276:immunology
D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D019013:CD40 Antigens; C497964:CD86 protein, human; D017931:DNA Primers; D018076:DNA, Complementary; D008562:Membrane Glycoproteins