title: Analysis of the functional WT1-specific T-cell repertoire in healthy donors reveals a discrepancy between CD4(+) and CD8(+) memory formation.
abstract: The Wilms' tumour-1 (WT1) protein is considered a prime target for cancer immunotherapy based on its presumptive immunogenicity and widespread expression across a variety of malignancies. However, little is known about the naturally occurring WT1-specific T-cell repertoire because self-derived antigens typically elicit low frequency responses that challenge the sensitivity limits of current detection techniques. In this study, we used highly efficient cell enrichment procedures based on CD137, CD154, and pHLA class I tetramer staining to conduct a detailed analysis of WT1-specific T cells from the peripheral blood. Remarkably, we detected WT1-specific CD4(+) and CD8(+) T-cell populations in the vast majority of healthy individuals. Memory responses specific for WT1 were commonly present in the CD4(+) T-cell compartment, whereas WT1-specific CD8(+) T cells almost universally displayed a naive phenotype. Moreover, memory CD4(+) and naive CD8(+) T cells with specificity for WT1 were found to coexist in some individuals. Collectively, these findings suggest a natural discrepancy between the CD4(+) and CD8(+) T-cell lineages with respect to memory formation in response to a self-derived antigen. Nonetheless, WT1-specific T cells from both lineages were readily activated ex vivo and expanded in vitro, supporting the use of strategies designed to exploit this expansive reservoir of self-reactive T cells for immunotherapeutic purposes.
authors.affiliation: Miltenyi Biotec GmbH, Bergisch Gladbach, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Schmied
authors.affiliation: Institute of Infection & Immunity, Cardiff University School of Medicine, Cardiff, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Gostick
authors.affiliation: Institute of Infection & Immunity, Cardiff University School of Medicine, Cardiff, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.affiliation: Centre for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.|Department I Internal Medicine, University Hospital Cologne, Cologne, Germany.
authors.forename: Hinrich
authors.initials: H
authors.lastname: Abken
authors.affiliation: Miltenyi Biotec GmbH, Bergisch Gladbach, Germany.
authors.forename: Mario
authors.initials: M
authors.lastname: Assenmacher
authors.affiliation: Miltenyi Biotec GmbH, Bergisch Gladbach, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Richter
mesh_terms: D000951:Antigens, Neoplasm / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D006801:Humans; D007156:Immunologic Memory; D008297:Male; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000276:immunology; D025721:WT1 Proteins / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D025721:WT1 Proteins; C583751:WT1 protein, human; D023201:CD40 Ligand
keywords: Wilms’ tumour-1 protein; antigen-specific T cells; self-antigen; tumour-associated antigen