Transplantation tolerance mediated by regulatory T cells in mice.
BACKGROUND
With potent suppressive effect on responder T cells, CD(4)(+)CD(25)(+) regulatory T (Treg) cells have become the focus of attention only recently and they may play an important role in transplantation tolerance. However, the mechanism of action is not clear. This study was designed to assess the possibility of using CD(4)(+)CD(25)(+) Treg cells to induce transplantation tolerance and to investigate their mechanism of action.


METHODS
CD(4)(+)CD(25)(+) Treg cells were isolated using magnetic cell separation techniques. Mixed lymphocyte reactions were used to assess the ability of Treg cells to suppress effector T cells. Before skin transplantation, various numbers of CD(4)(+)CD(25)(+) Treg cells, which have been induced using complex skin antigens from the donor, were injected into the host mice either intraperitoneally [0.5 x 10(5), 1 x 10(5), 2 x 10(5), 3 x 10(5), 4 x 10(5), or 5 x 10(5)] or by injection through the tail vein [5 x 10(3), 1 x 10(4), 2 x 10(4), 5 x 10(4), 1 x 10(5), 2 x 10(5)]. Skin grafts from two different donor types were used to assess whether the induced Treg cells were antigen-specific. The survival time of the allografts were observed. Single photon emission computed tomography was also used to determine the distribution of Treg cells before and after transplantation.


RESULTS
Treg cells have suppressive effect on mixed lymphocyte reactions. Grafts survived longer in mice receiving CD(4)(+)CD(25)(+) Treg cell injections than in control mice. There was a significant difference between groups receiving intraperitoneal injection of either 2 x 10(5) or 3 x 10(5) CD(4)(+)CD(25)(+) Treg cells and the control group (P < 0.05, respectively). Better results were achieved when Treg cells were injected via the tail vein than when injected intraperitoneally. The transplantation tolerance induced by CD(4)(+)CD(25)(+) Treg cells was donor-specific. Analysis of the localization of Treg cells revealed that Treg cells mainly migrated from the liver to the allografts and the spleen.


CONCLUSIONS
CD(4)(+)CD(25)(+)Treg cells can induce donor-specific transplantation tolerance. Cell-to-cell contact may be the primary mechanism by which Treg cells act on effector T cells.
Feng
Ning-han
NH
Department of Urology, Center of Kidney Transplantation, First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, China.
Wu
Hong-fei
HF
Wu
Jun
J
Zhang
Wei
W
Sui
Yuan-geng
YG
He
Hou-guang
HG
Zhang
Chun-lei
CL
Zheng
Jun-song
JS
D000818:Animals; D006084:Graft Rejection; D007108:Immune Tolerance; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D016038:Skin Transplantation / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*