Transplant long-surviving induced by CD40–CD40 ligand costimulation blockade is dependent on IFN-γ through its effect on CD4+CD25+ regulatory T cells

Abstract

BackgroundIFN-γ was documented to be commonly associated with acute rejection. In the present study, we investigated the role of IFN-γ in the transplant long-surviving induced by blocking CD40–CD40 ligand (CD40–CD40L) costimulation and its mechanisms. MethodsIFN-γ expression in cardiac allografts and spleens from syngeneic and allogeneic recipients with or without anti-CD40L monoclonal antibody (MR-1) treatment was examined by real-time RT-PCR. The grafts survival time in Wild type (IFN-γ+/+) and IFN-γ deficient (IFN-γ−/−) recipients was investigated. Mixed lymphocyte reaction (MLR) of CD4+ T cells and cytotoxic T lymphocyte (CTL) assay of CD8+ T cells were also studied. FoxP3 expression in allografts and spleens from IFN-γ+/+ or IFN-γ−/− recipients with MR-1 treatment was examined. Furthermore, FoxP3, IL-10 and CTLA-4 expressions and the suppressive capability of CD4+CD25+ regulatory T cells were examined. ResultsRejected allografts showed significantly higher IFN-γ expression than long-surviving allografts. Allograft survival was not prolonged in nonimmunosuppressed IFN-γ−/− mice. Administration of MR-1 induced long-term survival in 90.1% of IFN-γ+/+ recipients (98±6.6days) but failed to do so in IFN-γ−/− group (16.2±4.0days). IFN-γ−/− recipients facilitated the proliferation and CTL generation of T cells. The allografts and spleens from IFN-γ+/+ recipients contained higher FoxP3 expression than IFN-γ−/− recipients. Moreover, CD4+CD25+ T cells from IFN-γ+/+ recipients displayed a higher FoxP3 and IL-10 expression and suppressive capability. ConclusionIFN-γ plays an important role in the long-surviving induced by blocking CD40–CD40L through inhibiting the function of activated T cells and increasing suppressive capability of CD4+CD25+ regulatory T cells.