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Haematologica 2019 Volume 104(6):1136-1142
Hematopoiesis
CD150high CD4 T cells and CD150high regulatory T cells regulate hematopoietic stem cell quiescence via CD73
Yuichi Hirata,1,2,3,4 Miwako Kakiuchi,1,2,3 Simon C Robson5 and Joji Fujisaki1,2,6*
1Columbia Center for Translational Immunology, Columbia University College of Physicians and Surgeons, New York, NY, USA; 2Columbia Stem Cell Initiative, Columbia University College of Physicians and Surgeons, New York, NY, USA; 3Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA; 4MSD K.K., Tokyo, Japan; 5Department of Medicine, Liver Center and Transplantation Institute, Beth Israel Deaconess
6
Medical Center, Harvard Medical School, Boston, MA, USA and Department of Pediatrics,
Division of Hematology and Oncology, Columbia University College of Physicians and Surgeons, New York, NY, USA
ABSTRACT
Various extrinsic signals tightly control hematopoietic stem cell quies- cence. Our recent study showed that hematopoietic stem cells are
+
regulated by a special FoxP3 regulatory T-cell population with high
expression of a hematopoietic stem cell marker, CD150. Extracellular adenosine generated via a cell-surface ectoenzyme CD39 on CD150high reg- ulatory T cells maintained hematopoietic stem cell quiescence. It remains unclear how conventional T cells and the other cell-surface ectoenzyme, CD73, contribute to regulation of hematopoietic stem cells. This work shows that CD150high regulatory T cells as well as unique CD150high CD4+ conventional T cells regulate hematopoietic stem cells via CD73. Global CD73 deletion increased the numbers of hematopoietic stem cells, cycling stem cell frequencies, and levels of reactive oxygen species in hematopoiet- ic stem cells. In vivo antioxidant treatment inhibited the increase of hematopoietic stem cells in CD73 knockout mice, suggesting that CD73 maintains stem cell quiescence by preventing oxidative stress. High levels of CD73 expression were frequently found on CD150high regulatory T cells and CD150high FoxP3-CD4+ T cells within the bone marrow. Transfer of these CD150high regulatory T cells and CD150high CD4+ conventional T cells abolished the increase of hematopoietic stem cells in CD73 knockout mice. In addition, the increase of stem cells in CD73 knockout mice was also inhibited by pharmacological activation of adenosine receptor 2A which is highly expressed by hematopoietic stem cells. Taken together, these results suggest that CD73 of CD150high regulatory T cells and CD150high CD4+ con- ventional T cells protects hematopoietic stem cells from oxidative stress, maintaining stem cell quiescence via adenosine receptor 2A.
Introduction
The bone marrow (BM) microenvironment provides various cues to regulate hematopoietic stem cell (HSC) quiescence, self-renewal, and multilineage differen- tiation,1-4 and to protect HSC from various stresses, such as oxidative stress5 and toxic substances.6 Different mesenchymal subsets and megakaryocytes form a spe- cialized regulatory zone for HSC residence, called the niche, within the BM.1-4 It is thought that tight control of HSC quiescence and function helps to prevent HSC exhaustion and genetic mutation. Due to a growing demand for clinical BM trans- plantation, understanding how the BM microenvironment regulates HSC remains important.
Our recent study demonstrated that HSC were regulated by a unique popula- tion of regulatory T cells (Treg) with high expression of a HSC marker, CD150.7 These CD150high Treg frequently localized adjacent to HSC.7 Treg-mediated HSC regulation depended on a cell-surface ectoenzyme, CD39, which was highly
Correspondence:
JOJI FUJISAKI
jf2819@cumc.columbia.edu
Received: May 23, 2018.
Accepted: December 10, 2018. Pre-published: December 13, 2018.
doi:10.3324/haematol.2018.198283
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/6/1136
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