title: Antileukemic T-cell responses can be predicted by the composition of specific regulatory T-cell subpopulations.
abstract: Regulatory T cells (Treg) are important regulators of immune responses. In acute myeloid leukemia (AML) patients before/after immunotherapy (stem cell transplantation or donor lymphocyte infusion), their suppressive role can contribute to suppress severe graft-versus-host reactions, but also to impair antileukemic reactions. As leukemia-derived dendritic cells (DCleu) are known to improve the antileukemic functionality of T cells, we evaluated the composition and development of distinct Treg subtypes in AML patients (n=12) compared with healthy probands (n=5) under unstimulated conditions and during stimulation with DCleu-containing DC (DC) or blast-containing mononuclear cells (MNC) in 0- to 7-day mixed lymphocyte cultures by flow cytometry. T-cell subgroups in AML patients were correlated with antileukemic functionality before and after DC or MNC stimulation by functional fluorolysis assays. (1) AML patients' T cells presented with significantly higher frequencies of Treg subgroups in unstimulated T cells compared with healthy probands. (2) After 7 days of DC or MNC stimulation, all Treg subtypes generally increased; significantly higher frequencies of Treg subtypes were still found in AML patients. (3) Antileukemic cytotoxicity was achieved in 36% of T cells after MNC compared with 64% after DC stimulation. Antileukemic activity after DC but not after MNC stimulation correlated with significantly lower frequencies of Treg subtypes (CD8Treg/Teff/em reg). Furthermore, cut-off values for Treg subpopulations could be defined, allowing a prediction of antileukemic response. We demonstrate a crucial role of special Treg subtypes in the mediation of antileukemic functionality. High CD8 Treg, Teff/em reg, and CD39 T cells correlated clearly with a reduced antileukemic activity of T cells. DC stimulation of T cells contributes to overcome impaired antileukemic T-cell reactivity. Refined analyses in the context of clinical responses to immunotherapies and graft versus host reactions are required.
authors.affiliation: Department for Hematopoietic Cell Transplantation, Medicine Department 3, University Hospital of Munich, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Schick
authors.forename: Valentin
authors.initials: V
authors.lastname: Vogt
authors.forename: Marion
authors.initials: M
authors.lastname: Zerwes
authors.forename: Tanja
authors.initials: T
authors.lastname: Kroell
authors.forename: Doris
authors.initials: D
authors.lastname: Kraemer
authors.forename: Claus-Henning
authors.initials: CH
authors.lastname: Köhne
authors.forename: Andreas
authors.initials: A
authors.lastname: Hausmann
authors.forename: Raymund
authors.initials: R
authors.lastname: Buhmann
authors.forename: Johanna
authors.initials: J
authors.lastname: Tischer
authors.forename: Helga
authors.initials: H
authors.lastname: Schmetzer
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015703:Antigens, CD; D002454:Cell Differentiation; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D015470:Leukemia, Myeloid, Acute / Q000276:immunology* / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000276:immunology* / Q000473:pathology; D009367:Neoplasm Staging; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D055815:Young Adult
chemical_list: D015703:Antigens, CD