Page 245 - 2021_03-Haematologica-web

Letters to the Editor
Transfer of stem cell niche-residential regulatory
T cells prevents post-irradiation bone marrow injury
Post-irradiation bone marrow (BM) injury is a major dose-limiting side effect of radiation therapy for cancers.1 Irradiation generates free radicals which cause DNA damage and death of hematopoietic stem cells (HSC) and progenitor cells (HSPC), leading to depletion of BM and blood cells.1 There is a substantial unmet clinical need for new treatment strategies for post-irradiation BM injury. One of the potential therapeutic targets is the HSC niche which provides various cues to regulate HSC fate and function, and protect HSC from stress. Our recent studies have demonstrated that unique BM FoxP3+ regulatory T cells (Tregs) with high expression of a HSC marker, CD150, frequently localized adjacent to HSC, rendering the HSC niche an immunological sanctuary for stem cells, termed an immune privileged site.2-4 Little is known about roles of immune privilege in tissue injury. Here, we investigate roles and therapeutic utility of HSC niche-res- idential CD150high Tregs in post-irradiation BM injury. This work demonstrates that niche Treg-derived extracel- lular adenosine mitigates post-irradiation BM injury. Our
work further identifies niche Treg transfer and adenosine 2A receptor agonist treatment as promising treatment strategies to prevent BM injury.
Immune privilege was originally demonstrated decades ago within testis, placenta and hair follicle. In these tis- sues, multiple mechanisms conspire to prevent or sup- press the immune reaction, even enabling persistence of transplanted allogeneic (allo-) or xenogeneic grafts with- out immune suppressive therapy.5,6 Although more recent stem cell research has identified various tissue-commit- ted stem cells and their niches, little is known about whether these niches are broadly immune privileged. Our recent study demonstrated that the HSC niche with- in the BM accommodates unique potent CD150high Tregs, rendering HSC immune privileged.2-4 These CD150high Tregs comprise approximately 30% of BM Tregs and from 0.04% to approximately 0.07% of whole BM mononuclear cells. As compared to CD150low BM Tregs and lymph node Tregs, HSC niche-residential CD150high Tregs highly expressed cell-surface ectoenzymes CD39 and CD73 which generate extracellular adenosine, a nucleotide with potent immunosuppressive and tissue- protective effects.2,7 Niche Treg-derived adenosine pro-
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Figure 1. Reduction of bone marrow (BM) regulatory T cells (Tregs) and CD39 deletion in Tregs exacerbated post-irradiation BM failure. (A-E) Analysis of FoxP3cre-CXCR4fl/fl or FoxP3cre mice. fl: FoxP3cre-CXCR4fl/fl mice. wt: FoxP3cre. (A) Survival after 9 Gy total body irradiation (TBI). Pooled from three independent experiments. (B) Numbers of BM cells, hematopoietic stem progenitor cells (HSPC) and hematopoietic stem cells (HSC) on day 10 after 5 Gy TBI. N=3/group. (C) Death (7AAD+) frequencies in HSPC and HSC on day 10. N=3/group. (D and E) HSC numbers (D) and death frequencies (E) on day 28 after 8.5 Gy TBI. N=4/group. (F-H) Analysis of FoxP3cre-CD39fl/wt mice or FoxP3cre mice. fl: FoxP3cre-CD39fl/wt mice. wt: FoxP3cre mice. (F) Survival after 9 Gy TBI. Pooled from three independent experiments. (G) Numbers of BM cells, HSPC and HSC on day 28 after 8.5 Gy TBI in FoxP3cre-CD39fl/wt mice. N=3/group. (H) Death frequencies in HSPC and HSC on day 28 after 8.5 Gy TBI. N=3/group. Statistical analyses were performed with GraphPad Prism and EZR. Statistical significance was deter- mined using two-tailed t-test. For survival analysis, generalized Wilcoxon test was used. All data are presented as mean±standard deviation. 7-week-old mice were used in all studies. n: number. *P<0.05; **P<0.01; ***P=0.001.
haematologica | 2021; 106(3)
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