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Type: Journal article
Title: T-cell immune responses to Wilms tumor 1 protein in myelodysplasia responsive to immunosuppressive therapy
Author: Sloand, E.
Melenhorst, J.
Tucker, Z.
Pfannes, L.
Brenchley, J.
Yong, A.
Visconte, V.
Wu, C.
Gostick, E.
Scheinberg, P.
Olnes, M.
Douek, D.
Price, D.
Barrett, A.
Young, N.
Citation: Blood, 2011; 117(9):2691-2699
Publisher: American Society of Hematology
Issue Date: 2011
ISSN: 0006-4971
Statement of
Elaine M. Sloand, J. Joseph Melenhorst, Zachary C. G. Tucker, Loretta Pfannes, Jason M. Brenchley, Agnes Yong, Valeria Visconte, Colin Wu, Emma Gostick, Phillip Scheinberg, Matthew J. Olnes, Daniel C. Douek, David A. Price, A. John Barrett, and Neal S. Young
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.
Keywords: CD8-Positive T-Lymphocytes
Bone Marrow Cells
Chromosomes, Human, Pair 8
Myelodysplastic Syndromes
Receptors, Antigen, T-Cell, alpha-beta
WT1 Proteins
RNA, Messenger
HLA-A Antigens
HLA-A2 Antigen
Immunodominant Epitopes
Case-Control Studies
Gene Expression Regulation
Protein Structure, Quaternary
Rights: Copyright 2011 by The American Society of Hematology
DOI: 10.1182/blood-2010-04-277921
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