CD150high Bone Marrow Tregs Maintain Hematopoietic Stem Cell Quiescence and Immune Privilege via Adenosine

Abstract

A crucial player in immune regulation, FoxP3 regulatory T cells (Tregs) are drawing attention for their heterogeneity and noncanonical functions. Here, we describe a Treg subpopulation that controls hematopoietic stem cell (HSC) quiescence and engraftment. These Tregs highly expressed an HSC marker, CD150, and localized within the HSC niche in the bone marrow (BM). Specific reduction of BM Tregs achieved by conditional deletion of CXCR4 in Tregs increased HSC numbers in the BM. Adenosine generated via the CD39 cell surface ectoenzyme on niche Tregs protected HSCs from oxidative stress and maintained HSC quiescence. In transplantation settings, niche Tregs prevented allogeneic (allo-) HSC rejection through adenosine and facilitated allo-HSC engraftment. Furthermore, transfer of niche Tregs promoted allo-HSC engraftment to a much greater extent than transfer of other Tregs. These results identify a unique niche-associated Treg subset and adenosine as regulators of HSC quiescence, abundance, and engraftment, further highlighting their therapeutic utility.

Two to Tango: Dialog between Immunity and Stem Cells in Health and Disease

“…Like macrophages, Tregs display functional heterogeneity and plasticity as an apparent means of adaption to varying physiological states (Sakaguchi et al, 2013). T regs are potent suppressors of the immune response, where they function in preventing catastrophic autoimmunity (Josefowicz et al, 2012) A number of stem cell niches have a paucity of inflammatory cells in their vicinity, leading researchers to wonder whether these immune privileged sites might be possible residences for T reg (Fujisaki et al, 2011; Hirata et al, 2018). …”

“…In the absence of bone marrow T regs , HSCs were fewer in number and displayed increased sensitivity to oxidative stress (Hirata et al, 2018). T reg -derived adenosine, sensed directly by the HSC’s adenosine receptor, has been implicated in HSC responsiveness to oxidative stress and maintenance of quiescence (Figure 3A).…”

“…Rosenblum and colleagues recently reported that T reg numbers fluctuate during the normal hair cycle, peaking in telogen when stem cells are quiescent, and then reaching a low during anagen (Ali et al, 2017). Although it remains unclear how T regs influence hair cycling in their native setting, a role for T regs in maintaining stemness and quiescence would parallel the role of T regs in HSCs and ISCs (Ali et al, 2017; Biton et al, 2017; Fujisaki et al, 2011; Hirata et al, 2018). …”

Local exchange of metabolites shapes immunity

“…In the BM, Treg cells have been shown not only to regulate the niche compartment – and thereby influence B‐cell differentiation – but also to support maintenance of long‐lived plasma cells . Interestingly, a recent report suggests that niche Treg cells may be distinct from peripheral Treg cells by their high expression of the HSC marker CD150 and their capacity to release adenosine into their local environment, which in turn reduces oxidative stress in HSC . However, studies so far have not investigated whether the BM stroma contributes to Treg cell metabolism by provision of free fatty acids as described in peripheral tissues.…”

Regulation of regulatory T cells in cancer

“…Surprisingly, Treg cells were in dynamic equilibrium with hair‐regrowth phases, and influenced follicular stem cell quiescence by expression of the Notch1 ligand Jagged 1. Similarly, Treg cells play an active role in protecting the intestinal epithelial, and bone marrow stem cell niche . Finally, tissue‐resident Treg cells also express certain genes involved in epithelial cell repair, such as the growth factor amphiregulin ( Areg ), and thereby contribute to wound healing.…”