Prädiktive Relevanz regulatorischer T-Zellsubpopulationen nach Stimulation mit dendritischen Zellen leukämischer Abstammung für die antileukämische T-Zellantwort

Regulatory T-cells (Treg) are important regulators of immune
responses. In AML patients before/after immunotherapy
(stem-cell-transplantation (SZT) or donor-lymphocyte-infusion
(DLI)) their suppressive role can contribute to suppress severe
graft-versus-host-reactions (GVHD), but also to impair antileukemic
reactions. Aim: Since leukemia-derived dendritic-cells (DCleu) are
known to improve antileukemic functionality of T-cells we evaluated
the composition and development of distinct Treg-subtypes in
AML-pts (n=12) compared to healthy probands (n=5) under
unstimulated conditions and during stimulation with
DCleu-containing DC (‘DC’) or blast-containing mononuclear cells
(‘MNC’) in 0-7 days mixed lymphocyte cultures (MLC) by
flowcytometry. T-cell-subgroups in AML pts were correlated with
antileukemic functionality before and after ‘DC’ or ’MNC’
stimulation by functional fluorolysis-assays. Results: 1. AML-pts’
T-cells presented with significantly higher frequencies of
Treg-subgroups in unstimulated T-cells compared to 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-pts. 3. Antileukemic
cytotoxicity was achieved in 36% of T-cells after ‘MNC’- compared
to 64% after ‘DC’-stimulation. Antileukemic activity after ‘DC’ but
not after ‘MNC’-stimulation correlated with significantly lower
frequencies of Treg-subtypes (CD8+ Treg/Teff/em reg). Furthermore,
cut-off-values for Treg subpopulations could be defined allowing a
prediction of antileukemic response. Conclusion: We demonstrate a
crucial role of special Treg-subtypes in the mediation of
antileukemic functionality. High CD8+Treg, Teff/em reg and
CD39+T-Zellen clearly correlated with 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 immunotherapy and GVHD reactions
are required.