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Tnfrsf4-expressing regulatory T cells promote immune escape of chronic myeloid leukemia stem cells
Magdalena Hinterbrandner, … , Adrian F. Ochsenbein, Carsten Riether
Magdalena Hinterbrandner, … , Adrian F. Ochsenbein, Carsten Riether
Published November 2, 2021
Citation Information: JCI Insight. 2021;6(23):e151797. https://doi.org/10.1172/jci.insight.151797.
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Research Article Hematology Stem cells

Tnfrsf4-expressing regulatory T cells promote immune escape of chronic myeloid leukemia stem cells

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Abstract

Leukemia stem cells (LSCs) promote the disease and seem resistant to therapy and immune control. Why LSCs are selectively resistant against elimination by CD8+ cytotoxic T cells (CTLs) is still unknown. In this study, we demonstrate that LSCs in chronic myeloid leukemia (CML) can be recognized and killed by CD8+ CTLs in vitro. However, Tregs, which preferentially localized close to CD8+ CTLs in CML BM, protected LSCs from MHC class I–dependent CD8+ CTL–mediated elimination in vivo. BM Tregs in CML were characterized by the selective expression of tumor necrosis factor receptor 4 (Tnfrsf4). Stimulation of Tnfrsf4 signaling did not deplete Tregs but reduced the capacity of Tregs to protect LSCs from CD8+ CTL–mediated killing. In the BM of newly diagnosed CML patients, TNFRSF4 mRNA levels were significantly increased and correlated with the expression of the Treg-restricted transcription factor FOXP3. Overall, these results identify Tregs as key regulators of immune escape of LSCs and TNFRSF4 as a potential target to reduce the function of Tregs and boost antileukemic immunity in CML.

Authors

Magdalena Hinterbrandner, Viviana Rubino, Carina Stoll, Stefan Forster, Noah Schnüriger, Ramin Radpour, Gabriela M. Baerlocher, Adrian F. Ochsenbein, Carsten Riether

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Figure 7

Stimulation of Tnfrsf4-signaling reduces the capacity of Tregs to protect LSCs from CD8+ CTL–mediated killing.

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Stimulation of Tnfrsf4-signaling reduces the capacity of Tregs to protec...
(A) Representative FACS plots for the expression of Tnfrsf4 on CD4+Foxp3-GFP+ T cells (Tregs), CD4+Foxp3– T cells, CD8+ CTLs, L-Gr-1+ cells, and LSCs in the BM of Foxp3DTR CML mice. One representative out of 9 plots is depicted. Staining, black; isotype control, gray. (B) Frequency of CD4+Foxp3-GFP+ T cells, CD4+Foxp3– T cells, CD8+ CTLs, L-Gr-1+ cells, and LSCs in the BM of CML mice expressing Tnfrsf4 (n = 9 mice/cell subset). (C) LSCs from the BM of Foxp3DTR CML mice were cultured with BM CD8+ T cells and/or BM Tregs of the same mice pretreated for 2 hours with a Tnfrsf4 antibody (clone OX-86, 30 μg/mL) or respective control antibody at a ratio of 1:1:1 in triplicate followed by plating in methylcellulose. Colonies were enumerated 7 days later; 1-way ANOVA followed by Tukey’s post hoc test. (D and E) BL/6 CML mice were randomized to control IgG or anti-Tnfrsf4 antibody treatment (OX-86, 200 μg/mouse, i.p, for 6 times every second day, starting at day 12), and leukemia development and survival was monitored. (D) Number of L-Gr-1+ cells in the blood of IgG-treated and Tnfrsf4 antibody–treated BL/6 CML mice; 2-way ANOVA followed by Sidak’s multiple comparison test (n = 5 mice/group). (E) Kaplan-Meier survival curves of control IgG– and TNFRSF4 Ab–treated CML mice (IgG, n = 5; Tnfrsf4, n = 5); log-rank test. (F–J) CD8/Treg ratio in the BM, Treg numbers in the BM, spleen weight, numbers of L-Gr-1+ cells, and LSCs in the BM of control IgG– and TNFRSF4 Ab–treated CML mice (IgG, n = 5; Tnfrsf4, n = 4) 18 days after CML transplantation. t test. Data are displayed as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. One representative out of 2 independent experiments is shown.

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