A negative regulatory role in mouse cardiac transplantation for a splice variant of CD80.
BACKGROUND
Members of the B7 costimulatory protein family (CD80 and CD86) play a determining role in allograft rejection. Both CD80 and CD86 have naturally occurring splice variants whose roles in transplantation are unknown. Full length CD80 has two immunoglobulin (Ig)-like domains in the extracellular portion, IgC and IgV. In mouse, the isoform IgV-CD80 lacks the IgC-like domain. Here we analyzed the role of mouse IgV-CD80 in heart allograft rejection and search for equivalent splice variants in human.


METHODS
Mice made deficient for full-length CD80 but which retain expression of the shorter IgV-CD80 (CD80 mice) were used as donor or recipient of a heart allograft. Recipient animals were untreated or pretreated with alloantigen expressing cells and/or treated with CD80 and CTLA4 monoclonal antibodies (mAbs).


RESULTS
Recipients expressing IgV-CD80 but not full length CD80 exhibited a slight prolongation in survival of either wild-type (Wt) or CD80 grafts. More dramatically, CD80 animals pretreated with donor alloantigen exhibited permanent graft survival, whereas their Wt counterparts rejected their grafts with a median survival of 24 days. This prolonged survival was due to the expression of IgV-CD80 in recipients since treatment with CD80 mAb abrogated the beneficial effect observed. We identified and report here a similar isoform of CD80 from human cDNA encoding a putative soluble, IgV-containing protein.


CONCLUSIONS
IgV-CD80 bearing recipients show enhanced allograft survival especially after donor alloantigen pretreatment. This together with data from other species suggests that regulation delivered by splice variants of CD80 significantly modulates immunity and may be common across the species.
Bugeon
Laurence
L
Section of Immunology and Infection and CMMI, Division of Cell and Molecular Biology, Imperial College London, London, United Kingdom. l.bugeon@imperial.ac.uk
Wong
Kenneth K
KK
Rankin
Alasdair M
AM
Hargreaves
Roseanna E G
RE
Dallman
Margaret J
MJ
D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics*; D014644:Genetic Variation; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D006706:Homeostasis; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D023421:Models, Animal
D018122:B7-1 Antigen