Tnfrsf4-expressing regulatory T cells promote immune escape of chronic myeloid leukemia stem cells
Magdalena Hinterbrandner, Viviana Rubino, Carina Stoll, Stefan Forster, Noah Schnüriger, Ramin Radpour, Gabriela M. Baerlocher, Adrian F. Ochsenbein, Carsten Riether
Magdalena Hinterbrandner, Viviana Rubino, Carina Stoll, Stefan Forster, Noah Schnüriger, Ramin Radpour, Gabriela M. Baerlocher, Adrian F. Ochsenbein, Carsten Riether
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Research Article Hematology Stem cells

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

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 6

Tregs in the BM of CML mice are activated through interaction with MHC class II on leukemia cells resulting in immune escape of LSCs.

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Tregs in the BM of CML mice are activated through interaction with MHC c...
(A) L-Gr-1+ cells in blood from BL/6 and MHC class II–deficient (H2–/)– CML mice (n = 4–5 mice/group); 2-way ANOVA followed by Sidak’s multiple comparison test. (B–E) Spleen size, numbers of (C) L-lin–, (D) L–c-kithi cells and (E) LSCs in BM and (F) Colony formation capacity per mouse of BL/6 and H2–/– CML mice (18 day); Student’s t test. (G) BM cells of primary CML mice (day 18) were injected i.v. into lethally irradiated secondary BL/6 recipients, and survival was monitored; log-rank test. (H) Gating strategy to identify nTregs and eTregs; pregated on CD4+ Foxp3+ Tregs. (I) Numbers of eTregs within CD4+ T cell population in BL/6 and H2–/– CML. Dotted lines: range of eTregs observed in naive mice (n = 5); Student’s t test. (J and K) Frequencies and numbers of CD8+ T cells in BL/6 and H2–/– CML mice (day 18); t test. (L) BL/6 mice were treated i.p. with an αCD8 mAb (75 μg/injection) or control IgG at days –2, –1, 4, 9, and 14 (Groups: IgG, n = 4; αCD8, n = 5 mice/group). (M and N) Number of L-Gr-1+ cells in the blood and Kaplan-Meier survival graph of IgG- or αCD8-treated H2–/– CML mice (Groups: IgG, n = 4; αCD8, n = 5 mice/group); 2-way ANOVA followed by Sidak’s multiple comparison test and log-rank test. (O–Q)Number of L-lin– cells and LSCs in the BM and colony formation capacity per mouse of IgG-treated and αCD8-treated H2–/– CML mice (day 16; n = 4 mice/group); t test. (R) Kaplan-Meier survival graph from mice receiving BM cells of primary CML mice (day 16; n = 4 mice/group); log-rank test. Data are displayed as mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001. Dotted lines indicate time point experiment termination day 90.