Inhibitory feedback loop between tolerogenic dendritic cells and regulatory T cells in transplant tolerance.
An active role of T regulatory cells (Treg) and tolerogenic dendritic cells (Tol-DC) is believed important for the induction and maintenance of transplantation tolerance. However, interactions between these cells remain unclear. We induced donor-specific tolerance in a fully MHC-mismatched murine model of cardiac transplantation by simultaneously targeting T cell and DC function using anti-CD45RB mAb and LF 15-0195, a novel analog of the antirejection drug 15-deoxyspergualin, respectively. Increases in splenic Treg and Tol-DC were observed in tolerant recipients as assessed by an increase in CD4(+)CD25(+) T cells and DC with immature phenotype. Both these cell types exerted suppressive effects in MLR. Tol-DC purified from tolerant recipients incubated with naive T cells induced the generation/expansion of CD4(+)CD25(+) Treg. Furthermore, incubation of Treg isolated from tolerant recipients with DC progenitors resulted in the generation of DC with Tol-DC phenotype. Treg and Tol-DC generated in vitro were functional based on their suppressive activity in vitro. These results are consistent with the notion that tolerance induction is associated with a self-maintaining regulatory loop in which Tol-DC induce the generation of Treg from naive T cells and Treg programs the generation of Tol-DC from DC progenitors.
Min
Wei-Ping
WP
Department of Surgery, University of Western Ontario, London, Ontario, Canada. mweiping@uwo.ca
Zhou
Dejun
D
Ichim
Thomas E
TE
Strejan
Gill H
GH
Xia
Xiaoping
X
Yang
Jinming
J
Huang
Xuyan
X
Garcia
Bertha
B
White
David
D
Dutartre
Patrick
P
Jevnikar
Anthony M
AM
Zhong
Robert
R
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002450:Cell Communication / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D004357:Drug Synergism; D005246:Feedback / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology; D016027:Heart Transplantation / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D017493:Leukocyte Common Antigens / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D023001:Transplantation Tolerance / Q000187:drug effects / Q000276:immunology*; D016042:Transplantation, Heterotopic
D000911:Antibodies, Monoclonal; D006146:Guanidines; D007166:Immunosuppressive Agents; C434185:LF 150195; D017493:Leukocyte Common Antigens