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


METHODS
IFN-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.


RESULTS
Rejected 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±6.6 days) but failed to do so in IFN-γ(-/-) group (16.2±4.0 days). 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.


CONCLUSIONS
IFN-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.
Department of Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China. jiangxiao_feng@yahoo.cn
Xiao-Feng
XF
Jiang
Lei
L
Zhu
Zhe-Ming
ZM
Cui
Da-Wei
DW
Guo
Wen-Yu
WY
Sun
Lin
L
Lin
Yu-fu
YF
Tang
Xue-fan
XF
Wang
Jian
J
Liang
D000818:Animals; D000911:Antibodies, Monoclonal; D015703:Antigens, CD / Q000235:genetics; D019013:CD40 Antigens / Q000037:antagonists & inhibitors*; D023201:CD40 Ligand / Q000037:antagonists & inhibitors*; D060908:CTLA-4 Antigen; D051858:Forkhead Transcription Factors / Q000235:genetics; D006084:Graft Rejection; D006085:Graft Survival; D016027:Heart Transplantation; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D016753:Interleukin-10 / Q000235:genetics; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D019013:CD40 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D016753:Interleukin-10; D023201:CD40 Ligand; D007371:Interferon-gamma