title: T-cell immune responses to Wilms tumor 1 protein in myelodysplasia responsive to immunosuppressive therapy.
abstract: Clinical observations and laboratory evidence link bone marrow failure in myelodysplastic syndrome (MDS) to a T cell-mediated immune process that is responsive to immunosuppressive treatment (IST) in some patients. Previously, we showed that trisomy 8 MDS patients had clonally expanded CD8(+) T-cell populations that recognized aneuploid hematopoietic progenitor cells (HPC). Furthermore, microarray analyses showed that Wilms tumor 1 (WT1) gene was overexpressed by trisomy 8 hematopoietic progenitor (CD34(+)) cells compared with CD34(+) cells from healthy donors. Here, we show that WT1 mRNA expression is up-regulated in the bone marrow mononuclear cells of MDS patients with trisomy 8 relative to healthy controls and non-trisomy 8 MDS; WT1 protein levels were also significantly elevated. In addition, using a combination of physical and functional assays to detect the presence and reactivity of specific T cells, respectively, we demonstrate that IST-responsive MDS patients exhibit significant CD4(+) and CD8(+) T-cell responses directed against WT1. Finally, WT1-specific CD8(+) T cells were present within expanded T-cell receptor Vβ subfamilies and inhibited hematopoiesis when added to autologous patient bone marrow cells in culture. Thus, our results suggest that WT1 is one of the antigens that triggers T cell-mediated myelosuppression in MDS.
authors.affiliation: Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Sloand
authors.forename: J Joseph
authors.initials: JJ
authors.lastname: Melenhorst
authors.forename: Zachary C G
authors.initials: ZC
authors.lastname: Tucker
authors.forename: Loretta
authors.initials: L
authors.lastname: Pfannes
authors.forename: Jason M
authors.initials: JM
authors.lastname: Brenchley
authors.forename: Agnes
authors.initials: A
authors.lastname: Yong
authors.forename: Valeria
authors.initials: V
authors.lastname: Visconte
authors.forename: Colin
authors.initials: C
authors.lastname: Wu
authors.forename: Emma
authors.initials: E
authors.lastname: Gostick
authors.forename: Phillip
authors.initials: P
authors.lastname: Scheinberg
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Olnes
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Douek
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: A John
authors.initials: AJ
authors.lastname: Barrett
authors.forename: Neal S
authors.initials: NS
authors.lastname: Young
mesh_terms: D001854:Bone Marrow Cells / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016022:Case-Control Studies; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation; D015234:HLA-A Antigens / Q000737:chemistry / Q000276:immunology; D015789:HLA-A2 Antigen; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology; D007165:Immunosuppression Therapy; D009190:Myelodysplastic Syndromes / Q000276:immunology* / Q000628:therapy*; D020836:Protein Structure, Quaternary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D014314:Trisomy / Q000235:genetics / Q000276:immunology; D025721:WT1 Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D016056:Immunodominant Epitopes; D012333:RNA, Messenger; D016693:Receptors, Antigen, T-Cell, alpha-beta; D025721:WT1 Proteins