title: Cytokines affecting CD4(+) T regulatory cells in transplant tolerance. Interleukin-4 does not maintain alloantigen specific CD4(+)CD25(+) Treg.
abstract: IL-4 is thought to promote induction of transplantation tolerance and alloantigen-specific CD4(+)CD25(+) T regulatory cells (Treg). This study examined the effect of IL-4 on the induction and maintenance of the CD4(+) T regulatory cells (Treg) that mediate transplantation tolerance. Tolerance was induced in DA rats with PVG heterotopic cardiac allografts by a short course of cyclosporine. Naïve and tolerant lymphocytes, including the CD4(+) and CD4(+)CD25(+) T cell subsets, were assayed in mixed lymphocyte cultures with or without recombinant (r)IL-4 or other cytokines. The proliferation, cell surface and cytokine phenotype of these cells was examined, as was their capacity to adoptively transfer tolerance. rIL-4 enhanced the proliferation of naïve and tolerant lymphoid cells, including CD4(+) and CD4(+)CD25(+) T cells, but this was not alloantigen specific. Naïve or tolerant CD4(+) T cells cultured with rIL-4 and donor PVG antigen effected rapid graft rejection, even though before culture tolerant CD4(+) T cells transferred antigen-specific tolerance. These rIL-4 cultured CD4(+) T cells had a phenotype consistent with activated CD4(+)CD25(+)FoxP3(-) Th2 cells. While naïve natural CD4(+)CD25(+) T cells (nTreg) cultured with alloantigen and rIL-4 had enhanced proliferation and capacity to suppress rejection in vivo, the culture of tolerant CD4(+)CD25(+) T cells with alloantigen and rIL-4 could not sustain their proliferation against specific donor, nor their capacity to transfer tolerance to specific donor allograft. Thus, IL-4 promotes both regulatory and effector T cells early in the immune response, but once alloimmune tolerance is established, IL-4 promoted the activation of effector cells to mediate rejection and did not support alloantigen-specific Treg that could transfer specific tolerance.
authors.affiliation: Immune Tolerance Laboratory Faculty of Medicine, University of New South Wales, Sydney, Australia.
authors.forename: Karren M
authors.initials: KM
authors.lastname: Plain
authors.forename: Nirupama D
authors.initials: ND
authors.lastname: Verma
authors.forename: Giang T
authors.initials: GT
authors.lastname: Tran
authors.forename: Masaru
authors.initials: M
authors.lastname: Nomura
authors.forename: Rochelle
authors.initials: R
authors.lastname: Boyd
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Robinson
authors.forename: Suzanne J
authors.initials: SJ
authors.lastname: Hodgkinson
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Hall
mesh_terms: D064591:Allografts; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology / Q000494:pharmacology*; D007519:Isoantigens / Q000276:immunology*; D051381:Rats; D011917:Rats, Inbred Lew; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology / Q000473:pathology; D023001:Transplantation Tolerance / Q000187:drug effects*
chemical_list: D007519:Isoantigens; D015847:Interleukin-4
keywords: CD4(+)CD25(+)FoxP3(+) Treg; CPM; ConAsup; Counts per minute; IFN-γ; IFN-γ receptor; IFNGR; IL; IL-5 receptor alpha, specific for IL-5 binding; IL-5Rα; Interferon-gamma; Interleukin; Interleukin 4; MLC; Mixed lymphocyte culture; Natural T regulatory cells (CD4(+)CD25(+)FoxP3(+) T cell); Recombinant rat interleukin; Regulatory T cell; Supernatant from concanavalin A activated spleen cells; T regulatory cells induced from CD4(+)CD25(−) T cells; Th2 response; Transplantation tolerance; Ts1; Ts2; iTreg; nTreg; nTreg activated by IL-2 and alloantigen; nTreg activated by IL-4 and alloantigen; rIL