| Popis: |
BACKGROUND: Mesenchymal stromal cells (MSCs) exhibit immunosuppressive effects in vitro and in vivo. Therapeutic utility of MSC transfer for immune-mediated diseases has been long drawing attention. However, the role of endogenous MSCs in immune regulation in vivo has remained largely unclear. MSCs constitute the hematopoietic stem cell (HSC) niche within the bone marrow, perhaps leading to privilege of HSCs to evade immunity. Our recent study have demonstrated that potent niche-residential regulatory T cells (Tregs) endow HSCs with immune privilege, promoting allogeneic HSC engraftment. This Treg-mediated immune privilege depends on cell-surface ectoenzymes CD39 and CD73 on niche Tregs, which generate extracellular adenosine, a nucleotide that is known to suppress immunity and potentiate Tregs. Another niche constituents, leptin receptor-expressing (lepr+) perivascular MSCs, also highly express CD39 and CD73, prompting us to study their roles in immune privilege and allogeneic HSC engraftment. OBJECTIVE: The goal of the study is to test whether, like niche Tregs’ CD39, lepr+ MSCs’ CD39 positively regulates immune privilege of the HSC niche and promotes allogenic HSC engraftment,. STUDY DESIGN: We examined whether conditional deletion of CD39 in lepr+ cells in lepr-cre CD39-flox mice (B6 background) inhibits niche Tregs and decreases allo-HSC engraftment. We also compared these effects of CD39 deletion in lepr+ cells from those of CD39 deletion in Tregs in FoxP3-cre CD39-flox mice (B6). Allogenic HSC engraftment was assessed after transplantation of MHC-mismatched BALB/cJ BM cells following nonmyeloablative conditioning. Statistical significance was determined using two-tailed t-test or one-way ANOVA with Bonferroni posttest. RESULTS: Unexpectedly, CD39 deletion in lepr+ cells significantly increased and potentiated effector memory-like niche Tregs, promoting allogenic HSC engraftment. CD39 deletion in Tregs also significantly activated niche Tregs, while abrogating engraftment. CONCLUSION: Our observations suggest that adenosine from both Tregs and MSCs surprisingly inhibits niche Tregs, while adenosine from Tregs, but not from MSCs, acts as an effector molecule of immune privilege. This work identifies paradoxical effects of bone marrow MSCs and adenosine to activate immunity and inhibit immune privilege of the HSC niche. |
