Schick, Julia; Vogt, Valentin; Zerwes, Marion; Kröll, Tanja; Kraemer, Doris; Koehne, Claus-Henning; Hausmann, Andreas; Buhmann, Raymund; Tischer, Johanna; Schmetzer, Helga
Antileukemic T-cell Responses Can Be Predicted by the Composition of Specific Regulatory T-cell Subpopulations.
In: Journal of Immunotherapy, Vol. 36, Nr. 4: S. 223-237
Regulatory T cells (T-reg) 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 T-reg 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 T-reg subgroups in unstimulated T cells compared with healthy probands. (2) After 7 days of DC or MNC stimulation, all T-reg 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 T-reg subtypes (CD8(+) T-reg/T-eff/em reg). Furthermore, cut-off values for T-reg subpopulations could be defined, allowing a prediction of antileukemic response. We demonstrate a crucial role of special T-reg subtypes in the mediation of antileukemic functionality. High CD8(+) T-reg, T-eff/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.