Antigen-dependent suppression of alloresponses by Foxp3-induced regulatory T cells in transplantation.
Adoptive transfer of polyclonal CD4+CD25+ regulatory T cells (Treg) can tolerize transplantation alloresponses. Treg are activated via their specific TCR, but the antigen specificity of wild-type Treg remains elusive, and therefore controlling potency and duration of Treg activity in the transplantation setting is still not feasible. In this study, we used murine graft-versus-host disease (GVHD) as a model system to show that antigen-specific Treg suppress the response of T effector cells to alloantigens in vitro and prevent GVHD in vivo. The suppressive potential of antigen-specific Treg was much greater than that of polyclonal Treg. To acquire large numbers of antigen-specific Treg, we transduced CD4+CD25- cells with foxp3, and found that these foxp3-induced Treg suppress alloresponses in vitro and prevent GVHD in vivo as effectively as naturally derived CD4+CD25+ Treg. Furthermore, we used an antigen-specific CD4 Th1 clone as a source of foxp3-induced Treg after transduction with foxp3, and found those Treg to effectively prevent GVHD in an antigen-dependent manner. The findings of this study provide a basis for the concept that the onset and potency of the suppression by Treg can be regulated, and suggest a novel approach to enhance the feasibility and effectiveness of inducing tolerance by Treg as an adoptive immunotherapy in transplantation.
Albert
Michael H
MH
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, USA.
Liu
Yan
Y
Anasetti
Claudio
C
Yu
Xue-Zhong
XZ
D000818:Animals; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000637:transplantation*; D003433:Crosses, Genetic; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors; D006086:Graft vs Host Disease / Q000276:immunology* / Q000517:prevention & control; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007519:Isoantigens / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015375:Receptors, Interleukin-2 / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018417:Th1 Cells / Q000276:immunology; D014161:Transduction, Genetic
D015704:CD4 Antigens; D004268:DNA-Binding Proteins; D018984:Epitopes, T-Lymphocyte; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007519:Isoantigens; D015375:Receptors, Interleukin-2