title: CD4+CD25+ T cells alloactivated ex vivo by IL-2 or IL-4 become potent alloantigen-specific inhibitors of rejection with different phenotypes, suggesting separate pathways of activation by Th1 and Th2 responses.
abstract: CD4(+)CD25(+)Foxp3(+) T cells are regulatory/suppressor cells (Tregs) that include non-antigen (Ag)-specific as well as Ag-specific Tregs. How non-Ag-specific naive CD4(+)CD25(+) Treg develop into specific Tregs is unknown. Here, we generated adaptive Tregs by culture of naive CD4(+)CD25(+)Foxp3(+) T cells with allo-Ag and either interleukin-2 (IL-2) or IL-4. Within days, IL-2 enhanced interferon-gamma receptor (Ifngammar) and Il-5 mRNA and IL-4 induced a reciprocal profile with de novo IL-5Ralpha and increased IFN-gamma mRNA expression. Both IL-2- and IL-4-alloactivated CD4(+)CD25(+) Tregs within 3 to 4 days of culture had enhanced capacity to induce tolerance to specific donor but not to third-party cardiac allografts. These hosts became tolerant as allografts functioned more than 250 days, with a physiologic ratio of less than 10% CD4(+)CD25(+)Foxp3(+) T cells in the CD4(+) population. CD4(+)CD25(+) T cells from tolerant hosts given IL-2-cultured cells had increased Il-5 and Ifngammar mRNA. Those from hosts given IL-4-cultured cells had enhanced IL-5Ralpha mRNA expression and IL-5 enhanced their proliferation to donor but not third-party allo-Ag. Thus, IL-2 and IL-4 activated allo-Ag-specific Tregs with distinct phenotypes that were retained in vivo. These findings suggested that T-helper 1 (Th1) and Th2 responses activate 2 pathways of adaptive Ag-specific Tregs that mediate tolerance. We propose they be known as T-suppressor 1 (Ts1) and Ts2 cells.
authors.affiliation: Faculty of Medicine, University of New South Wales and Department of Medicine, Liverpool Hospital, Liverpool, Australia.
authors.forename: Nirupama D
authors.initials: ND
authors.lastname: Verma
authors.forename: Karren M
authors.initials: KM
authors.lastname: Plain
authors.forename: Masaru
authors.initials: M
authors.lastname: Nomura
authors.forename: Giang T
authors.initials: GT
authors.lastname: Tran
authors.forename: Catherine
authors.initials: C
authors.lastname: Robinson
authors.forename: Rochelle
authors.initials: R
authors.lastname: Boyd
authors.forename: Suzanne J
authors.initials: SJ
authors.lastname: Hodgkinson
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Hall
mesh_terms: D000818:Animals; D020170:Caspase 1 / Q000096:biosynthesis / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D007376:Interleukin-2 / Q000096:biosynthesis / Q000276:immunology*; D007519:Isoantigens / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D009206:Myocardium / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D012333:RNA, Messenger / Q000096:biosynthesis / Q000276:immunology; D051381:Rats; D011917:Rats, Inbred Lew; D017471:Receptors, Interferon / Q000096:biosynthesis / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D023001:Transplantation Tolerance; D000096743:Interferon gamma Receptor
chemical_list: D020170:Caspase 1; D016207:Cytokines; D007376:Interleukin-2; D007519:Isoantigens; D012333:RNA, Messenger; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor