Cardiac allograft acceptance induced by blockade of CD40-CD40L costimulation is dependent on CD4+CD25+ regulatory T cells.
BACKGROUND
We have demonstrated previously that CD4(+)CD25(+) regulatory T cells (Treg) are important for spontaneous hepatic allograft tolerance. In this study, we examine the role of Treg in cardiac allograft acceptance induced by blockade of the CD40-CD40L pathway.


METHODS
A heterotopic heart transplant model of major histocompatibility complex-mismatched mice was performed. Expression of forkhead/winged helix transcription factor (FoxP3) and/or the number of CD4(+)CD25(+) T cells in allografts and spleens were examined. The effect of Treg from the recipient or the donor on the induction and maintenance of long-term allograft survival was determined. Histologic analyses were also performed. The effects of Treg on CD4(+) and CD8(+) T cells were assessed.


RESULTS
The levels of FoxP3 and/or CD4(+)CD25(+) T cells increased in long-surviving allografts and spleens. Depletion of Treg in the recipients but not the donors before transplantation caused rejection. Histologic analyses of allografts with Treg depletion showed extensive leukocyte infiltration and tissue destruction. However, delayed depletion of Treg in long-surviving recipients did not shorten their survival. Treg depletion increased the function of CD4(+) and CD8(+) T cells.


CONCLUSIONS
Treg in the recipient but not in the donor is essential for long-term survival induced by CD40-CD40L blockade by inhibiting the function of CD4(+) and CD8(+) T cells; however, Treg are not important for maintenance. Both allograft and spleen are critical for induction of successful long-term survival.
Jiang
Xiaofeng
X
Department of Surgery, Fourth Affiliated Hospital, China Medical University, Shenyang, China. jiangxiao_feng@yahoo.cn
Sun
Wenyu
W
Guo
Dawei
D
Cui
Zheming
Z
Zhu
Lei
L
Lin
Lin
L
Tang
Yufu
Y
Wang
Xuefan
X
Liang
Jian
J
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000502:physiology*; D023201:CD40 Ligand / Q000502:physiology*; D006084:Graft Rejection; D006085:Graft Survival; D016027:Heart Transplantation / Q000276:immunology* / Q000401:mortality; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014184:Transplantation, Homologous
D019013:CD40 Antigens; C508018:Il2ra protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D023201:CD40 Ligand