title: Isolation of human MHC class II-restricted T cell receptors from the autologous T-cell repertoire with potent anti-leukaemic reactivity.
abstract: Adoptive transfer of T cells genetically modified with tumour-specific T-cell receptors (TCR) is a promising novel approach in the treatment of cancer. We have previously isolated an allorestricted MHC class I-restricted TCR with specificity for Formin-like protein 1 (FMNL1) with potent activity against chronic lymphocytic leukaemia cells. CD4(+)  T cells have been described to be highly important for tumour elimination although TCR derived from CD4(+)  T cells with anti-tumour reactivity have been only rarely described. In this study we aimed to isolate MHC class-II-restricted CD4(+)  T cells and TCR with specificity for leukaemia antigens. We used professional antigen-presenting cells pulsed with the leukaemia-associated and tumour-associated antigen FMNL1 for stimulation of autologous T cells in vitro. We isolated two CD4(+)  HLA-DR-restricted T-cell clones and T-cell-derived TCR with so far unknown specificity but high reactivity against lymphoma cells and native malignant cells derived from HLA-matched patients with diverse leukaemias. Moreover, characterization of the TCR after TCR gene transfer revealed that specific characteristics of isolated TCR as reactivity in response to Toll-like receptors were transferable on effector cells. Our results have a major impact on the development of novel immunotherapies. They demonstrate that TCR with potent HLA-DR-restricted anti-leukaemic reactivity against so far undefined self-restricted antigens can be isolated from the healthy autorestricted CD4(+)  T-cell repertoire and these TCR are highly interesting candidate tools for novel immunotherapies.
authors.affiliation: Medizinische Klinik III, Innere Medizin mit Schwerpunkt Hämatologie und Onkologie, Technische Universität München, Münich.
authors.forename: Luise U
authors.initials: LU
authors.lastname: Weigand
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Liang
authors.forename: Sabine
authors.initials: S
authors.lastname: Schmied
authors.forename: Sabine
authors.initials: S
authors.lastname: Mall
authors.forename: Richard
authors.initials: R
authors.lastname: Klar
authors.forename: Oliver J
authors.initials: OJ
authors.lastname: Stötzer
authors.forename: Christoph
authors.initials: C
authors.lastname: Salat
authors.forename: Katharina
authors.initials: K
authors.lastname: Götze
authors.forename: Josef
authors.initials: J
authors.lastname: Mautner
authors.forename: Christian
authors.initials: C
authors.lastname: Peschel
authors.forename: Angela M
authors.initials: AM
authors.lastname: Krackhardt
mesh_terms: D019070:Cell Lineage; D002478:Cells, Cultured; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology*; D015470:Leukemia, Myeloid, Acute / Q000276:immunology*; D008024:Ligands; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology
chemical_list: D000949:Histocompatibility Antigens Class II; D008024:Ligands; D011948:Receptors, Antigen, T-Cell