title: IFN-gamma production by alloantigen-reactive regulatory T cells is important for their regulatory function in vivo.
abstract: The significance of cytokine production by CD4(+) regulatory T (T reg) cells after antigen exposure in vivo and its impact on their regulatory activity remains unclear. Pretreatment with donor alloantigen under the cover of anti-CD4 therapy generates alloantigen reactive T reg cells that can prevent rejection of donor-specific skin grafts that are mediated by naive CD45RB(high)CD4(+) T cells. To examine the kinetics and importance of cytokine gene transcription by such alloantigen-reactive T reg cells, pretreated mice were rechallenged with donor alloantigen in vivo. CD25(+)CD4(+) T cells, but not CD25(-)CD4(+) T cells, showed a fivefold increase in IFN-gamma mRNA expression within 24 h of re-encountering alloantigen in vivo. This expression kinetic was highly antigen-specific and was of functional significance. Neutralizing IFN-gamma at the time of cotransfer of alloantigen reactive T reg cells, together with CD45RB(high)CD4(+) effector T cells into Rag(-/-) skin graft recipients, resulted in skin graft necrosis in all recipients; the generation and function of alloantigen-reactive T reg cells was impaired dramatically in IFN-gamma-deficient mice. These data support a unique role for IFN-gamma in the functional activity of alloantigen-reactive T reg cells during the development of operational tolerance to donor alloantigens in vivo.
authors.affiliation: Nuffield Department of Surgery, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, England, UK. birgit.sawitzki@charite.de
authors.forename: Birgit
authors.initials: B
authors.lastname: Sawitzki
authors.forename: Cherry I
authors.initials: CI
authors.lastname: Kingsley
authors.forename: Vanessa
authors.initials: V
authors.lastname: Oliveira
authors.forename: Mahzuz
authors.initials: M
authors.lastname: Karim
authors.forename: Manuela
authors.initials: M
authors.lastname: Herber
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Wood
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D015704:CD4 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D007371:Interferon-gamma / Q000378:metabolism*; D007519:Isoantigens / Q000276:immunology*; D017493:Leukocyte Common Antigens / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009841:Oligonucleotides; D012333:RNA, Messenger / Q000378:metabolism*; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D016038:Skin Transplantation / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D007519:Isoantigens; D009841:Oligonucleotides; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens