Transplantation tolerance induced by regulatory T cells: in vivo mechanisms and sites of action.
The mechanisms by which CD4(+)CD25(+)Foxp3(+) T (Treg) cells regulate effector T cells in a transplantation setting and their in vivo homeostasis still remain to be clarified. Using a mouse adoptive transfer model, we analyzed the in vivo expansion, trafficking, and effector function of alloreactive T cells and donor-specific Treg cells, in response to a full-thickness skin allograft. Fluorescent-labeled CD4(+)CD25(-) and antigen-specific Treg cells were transferred alone or co-injected into syngeneic BALB/c-Nude recipients transplanted with skins from (C57BL/6 x BALB/c) F1 donors. Treg cells divided in vivo, migrated and accumulated in the allograft draining lymph nodes as well as within the graft. The co-transfer of Treg cells did not modify the early activation and homing of CD4(+)CD25(-) T cells in secondary lymphoid organs. However, in the presence of Treg cells, alloreactive CD4(+)CD25(-) T cells produced significantly less IFN-gamma and were present in reduced numbers in the secondary lymphoid organs. Furthermore, time-course studies showed that Treg cells were recruited into the allograft at a very early stage after transplantation and effectively prevented the infiltration of effector T cells. In conclusion, suppression of rejection requires the early recruitment to the site of antigenic challenge of donor-specific Treg cells, which then mainly regulate the effector arm of T cell alloresponses.
Golshayan
Dela
D
Transplantation Centre and Transplantation Immunopathology Laboratory, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne University, 1011 Lausanne, Switzerland. dela.golshayan@chuv.ch
Wyss
Jean-Christophe
JC
Abulker
Caroline Wyss
CW
Schaefer
Stephan C
SC
Lechler
Robert I
RI
Lehr
Hans-Anton
HA
Pascual
Manuel
M
D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002465:Cell Movement / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016038:Skin Transplantation / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000502:physiology; D023001:Transplantation Tolerance / Q000276:immunology*; D014184:Transplantation, Homologous / Q000276:immunology* / Q000473:pathology