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Letters to the Editor
in irradiated FoxP3cre-CXCR4fl/fl mice (Figure 1F-H and Online Supplementary Figure 1D-F), suggesting Treg- derived adenosine as a critical mediator of Tregs to miti- gate post-irradiation BM injury. The therapeutic utility of niche Treg transfer was further investigated. Lethally- irradiated (9.5 Gy) B6 mice received tail vein injection of CD150high BM Tregs, CD150low BM Tregs or LN Tregs (CD4+CD3+NK1.1-FoxP3-YFP cells isolated from B6 FoxP3-YFP mice) on day -2. Transfer of as few as 30,000 CD150high BM Tregs per mouse rescued 9.5 Gy-irradiated mice, while transfer of CD150low BM Tregs or LN Tregs did not influence post-irradiation mouse mortality (Figure 2A). Consistently, transfer of CD150high BM Tregs, but not of CD150low BM or LN Tregs, improved recovery of the HSPC pool, decreasing post-irradiation HSPC death (Figure 2B and C, and Online Supplementary Figure S2). Next, the mechanism which confers niche Treg transfer with higher therapeutic efficacy was investigated. Our previous study has demonstrated that BM homing effica- cy of CD150high BM Tregs was equivalent to that of other Tregs.2 We examined whether niche Tregs’ therapeutic effect is attributed to CD39 which is highly expressed on CD150high BM Tregs as compared to other Tregs.2 Transfer of CD150high BM Tregs isolated from FoxP3cre-CD39fl/fl mice did not influence post-irradiation mouse mortality (Figure 2D), suggesting that therapeutic effect of niche Treg transfer depends on Treg-derived adenosine which was previously shown to protect HSPC from oxidative stress via A2ARs on HSPC.2 Consistently, A2AR agonist treatment (PSB0777;7 Tocris; 25 mg/dose; i.p. daily from day -2 till day 7) rescued 9.5 Gy-irradiated mice (Figure 2E).
Taken together, these observations demonstrate pro- tective roles of HSC niche-residential Tregs and their product, adenosine, in post-irradiation BM injury, further identifying niche Treg transfer and A2AR agonist treat- ment as new strategies to prevent BM injury. This report for the first time shows treatment utility of transferring niche Tregs for tissue injury, opening up new strategies to promote tissue regeneration or to counteract radiotoxici- ty following radiation therapy or nuclear terrorism. Our work is in line with a recent growing interest in non- canonical, tissue-protective effects of Tregs within mus- cle, lung, and hair follicle,8-12 while numbers of isolatable Tregs from these tissues are too low for transfer. It would be interesting to test whether transfer of HSC niche-resi- dential Tregs is effective in improving the outcome of injury of other tissues, as well as other BM failures, including acquired aplastic anemia which is hematopoiesis failure HSPC. It remains unknown how frequently muscle and lung Tregs reside in the stem cell niche and whether there is any immune privilege in other tissue-committed stem cell niches besides hair follicle and HSC niche.2-4,11,12 Testing whether niches broadly pos- sess immune privilege or harbor Tregs is warranted. Human BM Tregs were previously shown to exhibit higher suppressive potential in vitro than other Tregs,13 suggesting the possibility that human Tregs confer immune privilege to HSC. In summary, this work indi- cates that immune privilege, niche Tregs, and adenosine
represent promising therapeutic targets for tissue injury.
Miwako Kakiuchi,1,2,3* Yuichi Hirata,1,2,3* Simon C. Robson4,5 and Joji Fujisaki1,2,3,4,5
1Columbia Center for Translational Immunology, Columbia University College of Physicians and Surgeons, New York, NY; 2Columbia Stem Cell Initiative, Columbia University College of Physicians and Surgeons, New York, NY; 3Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York, NY; 4Center for Inflammation Research, Department of Anesthesia, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA and 5Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
*MK and YH contributed equally as co-first authors. Correspondence:
JOJI FUJISAKI - jfujisak@bidmc.harvard.edu doi:10.3324/haematol.2019.221820
Disclosures: no conflicts of interest to disclose.
Contributions: MK and YH performed all the experiments;
SCR provided the expertise in using CD39fl mice; YH, MK and JF analyzed and interpreted all the data; JF wrote the paper.
Funding: this work was supported by ASH Junior Faculty Basic Science Scholar Award ASOH CU15-2897 (to JF), NIH NHLBI 1R01HL129506-01A1 (to JF), NIH NHLBI R01HL145154-01 (to JF), and NIH NIDDK R01DK121889 (to JF).
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