title: Distinct effects of IL-18 on the engraftment and function of human effector CD8 T cells and regulatory T cells.
abstract: IL-18 has pleotropic effects on the activation of T cells during antigen presentation. We investigated the effects of human IL-18 on the engraftment and function of human T cell subsets in xenograft mouse models. IL-18 enhanced the engraftment of human CD8(+) effector T cells and promoted the development of xenogeneic graft versus host disease (GVHD). In marked contrast, IL-18 had reciprocal effects on the engraftment of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) in the xenografted mice. Adoptive transfer experiments indicated that IL-18 prevented the suppressive effects of Tregs on the development of xenogeneic GVHD. The IL-18 results were robust as they were observed in two different mouse strains. In addition, the effects of IL-18 were systemic as IL-18 promoted engraftment and persistence of human effector T cells and decreased Tregs in peripheral blood, peritoneal cavity, spleen and liver. In vitro experiments indicated that the expression of the IL-18Ralpha was induced on both CD4 and CD8 effector T cells and Tregs, and that the duration of expression was less sustained on Tregs. These preclinical data suggest that human IL-18 may have use as an adjuvant for immune reconstitution after cytotoxic therapies, and to augment adoptive immunotherapy, donor leukocyte infusions, and vaccine strategies.
authors.affiliation: Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Carroll
authors.forename: Carmine
authors.initials: C
authors.lastname: Carpenito
authors.forename: Xiaochuan
authors.initials: X
authors.lastname: Shan
authors.forename: Gwenn
authors.initials: G
authors.lastname: Danet-Desnoyers
authors.forename: Ronghua
authors.initials: R
authors.lastname: Liu
authors.forename: Shuguang
authors.initials: S
authors.lastname: Jiang
authors.forename: Steven M
authors.initials: SM
authors.lastname: Albelda
authors.forename: Tatiana
authors.initials: T
authors.lastname: Golovina
authors.forename: George
authors.initials: G
authors.lastname: Coukos
authors.forename: James L
authors.initials: JL
authors.lastname: Riley
authors.forename: Zdenka L
authors.initials: ZL
authors.lastname: Jonak
authors.forename: Carl H
authors.initials: CH
authors.lastname: June
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006086:Graft vs Host Disease / Q000378:metabolism; D006801:Humans; D020382:Interleukin-18 / Q000378:metabolism*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008954:Models, Biological; D009368:Neoplasm Transplantation; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
chemical_list: D020382:Interleukin-18