Antileukemic T-cell Responses Can Be Predicted by the Composition of Specific Regulatory T-cell Subpopulations

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.