Bone marrow or stem cell transplantation
Although the stem cell niche has been extensively studied as a site which regulates stem cell fate or functions, immunological attributes of the niche have remained largely unexplored. The locations of germline and embryonic stem cells, testis and placenta, were known to be immunological sanctuaries for stem cells, termed immune privileged (IP) sites. In these tissues, multiple mechanisms conspire to prevent immune attack, even enabling persistence of transplanted allogeneic or xenogeneic grafts without immune suppressive therapy. Little remains known about whether tissue-committed stem cell niches are broadly IP sites. We examined whether the hematopoietic stem cell (HSC) niche within the bone marrow (BM) serves as an IP site. We showed that unique FoxP3+ regulatory T cells (Tregs) with high expression of an HSC marker, CD150, frequently localized adjacent to HSCs. Extracellular adenosine derived from CD150high niche-residential Tregs enabled allo-HSC persistence without immune suppression, promoting engraftment following nonmyeloablative conditioning. Moreover, transfer of niche Tregs improved engraftment to a much greater extent than transfer of other Tregs. In non-transplantation settings, niche Tregs and their product, adenosine, protected endogenous HSCs from oxidative and radiation stresses and maintained HSC quiescence, further mitigating post-irradiation hematopoiesis failure. Finally, transfer of niche Tregs and adenosine receptor agonist treatment rescued lethally-irradiated mice from critical hematopoiesis failure. These results indicate that niche Tregs and adenosine render the HSC niche an immunological sanctuary for transplanted and endogenous HSCs from immune attack and stress. Our work further identifies therapeutic utility of transferring niche-residential Tregs for stem cell transplantation and tissue injury.