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 1

Thymic-derived effector Tregs accumulate in the BM of CML mice.

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Thymic-derived effector Tregs accumulate in the BM of CML mice. (A) Dist...
(A) Distribution of Foxp3+ Tregs in CML BM (day 14). Scale bar: 200 μm; n = 8 mice. (B and C) Distribution of Foxp3+ Tregs in the BM of (B) CML mice (n = 8) and (C) naive mice (n = 9) in respect to CTLs (scale bar: 50 μm; Foxp3, brown; CD8, red). Black circles, Foxp3+ cells; Red circles, CTLs close to Tregs. (D) Frequency of Tregs located close to CTLs in the BM naive and CML mice (naive: n = 9 mice; CML, n = 8 mice). Close proximity was defined as a distance of ≤ 2 cell nuclei; t test. (E) Frequency of BM Tregs within total CD4+ T cell population in naive (n = 11) and CML (n = 14) Foxp3DTR mice; t test. (F) Correlation between frequencies of Tregs (within total CD4+ T cells) and L-Gr-1+ cells in the BM of Foxp3DTR CML mice (n = 14); Pearson correlation (2-sided). (G) Viability of Tregs and Tconv from naive and Foxp3DTR CML mice (naive: n = 5 mice; CML: n = 9 mice); t test. (H and I) Proliferation of (H) BM Tregs and (I) Tconv from naive and Foxp3DTR CML mice (naive, n = 5 mice; CML, n = 5 mice). (J) Representative histogram for Helios+ thymic-derived Tregs (tTregs) and Helios– peripheral-induced Tregs (pTregs) in the BM of naive (n = 11) and CML Foxp3DTR mice (n = 8). Pregated on CD4+Foxp3-GFP+ Tregs. Staining: beige (naive) and black (CML); isotype: green; t test. (K) Representative zebra plot for naive/resting Tregs (nTregs) and effector Tregs (eTregs) in the BM of naive (n = 5) and CML Foxp3DTR mice (n = 5); t test. (L–O) MFI Foxp3 expression (GFP+), ΔMFI of Ctla-4, Gitr and Tgf-β1 on CD4+Foxp3-GFP+ Tregs in the BM naive (n = 4) and CML Foxp3DTR mice (n = 4–8); t test. ΔMFI, staining-isotype. Data are displayed as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 and ****P < 0.0001.