title: Absence of inducible costimulator on alloreactive T cells reduces graft versus host disease and induces Th2 deviation.
abstract: Inducible costimulator (ICOS) is expressed on activated and memory T cells and is involved in the regulation of cytokine production. We studied the role of ICOS on alloreactive T cells in graft versus host disease (GVHD) and determined that ICOS expression was up-regulated on alloreactive T cells in recipients of an allogeneic hematopoietic stem cell transplantation (allo-HSCT) with GVHD. We compared ICOS-/- T cells with wild-type (WT) T cells in 2 GVHD models. In both models, recipients of ICOS-/- T cells demonstrated significantly less GVHD morbidity and mortality, which was associated with less intestinal and hepatic GVHD but increased cutaneous GVHD. In addition, recipients of ICOS-/- donor T cells displayed a slight decrease in graft versus leukemia (GVL) activity. Further analysis of alloreactive ICOS-/- T cells showed no defect in activation, proliferation, cytotoxicity, and target organ infiltration. Recipients of ICOS-/- T cells had decreased serum levels of interferon-gamma (IFN-gamma), while interleukin-4 (IL-4) and IL-10 levels were increased, suggesting that alloreactive ICOS-/- T cells are skewed toward T helper-2 (Th2) differentiation. These data suggest a novel role for ICOS in the regulation of Th1/Th2 development of activated T cells. In conclusion, alloreactive ICOS-/- donor T cells induce less GVHD due to a Th2 immune deviation while GVL activity is slightly diminished.
authors.affiliation: Department of Medicine and ImmunologyMemorial Sloan-Kettering Cancer Center, Kettering 406D, Mailbox 111, 1275 York Ave, New York, NY 10021, USA.
authors.forename: Vanessa M
authors.initials: VM
authors.lastname: Hubbard
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Eng
authors.forename: Teresa
authors.initials: T
authors.lastname: Ramirez-Montagut
authors.forename: Kartono H
authors.initials: KH
authors.lastname: Tjoe
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Muriglan
authors.forename: Adam A
authors.initials: AA
authors.lastname: Kochman
authors.forename: Theis H
authors.initials: TH
authors.lastname: Terwey
authors.forename: Lucy M
authors.initials: LM
authors.lastname: Willis
authors.forename: Rafaella
authors.initials: R
authors.lastname: Schiro
authors.forename: Glen
authors.initials: G
authors.lastname: Heller
authors.forename: George F
authors.initials: GF
authors.lastname: Murphy
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.forename: Onder
authors.initials: O
authors.lastname: Alpdogan
authors.forename: Marcel R M
authors.initials: MR
authors.lastname: van den Brink
mesh_terms: D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation; D060889:Inducible T-Cell Co-Stimulator Protein; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein