Although hematopoietic stem cells (HSCs) have been extensively studied in transplantation and cancer, immunological properties of the HSC niche have remained largely unexplored. The testis and placenta act as immunological sanctuaries for embryonic and germline stem cells, and are termed immune privileged sites. In these tissues, allogeneic (allo-) or xenogeneic grafts persist long-term, even without immune suppressive therapy. Little is known about whether tissue-committed stem cell niches are broadly immune privileged. Our current R01 has tested whether the HSC niche within the bone marrow (BM) acts as an immune privileged site that shields both allo-HSCs and leukemic stem cells (LSCs) from immune attack. We have demonstrated that distinctly activated niche-residential FoxP3+ regulatory T cells (Tregs) render such HSCs immune privileged. Such niche Tregs enable the persistence of allo-HSCs in non-conditioned immune competent mice, while promoting engraftment. Niche Tregs also shield LSCs, leading to therapeutic resistance. To discover further fundamental insights into immune privilege, this R01 renewal application proposes the following extensions of study to characterize: A) niche Tregs; B) highly immune-privileged, highly primitive HSCs/LSCs, amongst other stem cells; and C) highly immunoprotective niches, amongst other HSC niche locations. There has remained a long-standing controversy as to whether the HSC niche localizes at BM sinusoids, arterioles, or the bone surface. This controversy may be at least partially explained by potential heterogeneity in HSCs. We expect that immune privilege identifies the top of the hierarchy within heterogenous HSCs and niches. The proposal will decipher the crosstalk among niche Tregs, highly immune-privileged HSCs/LSCs, and highly immunoprotective niches, and define their roles in allo-HSC transplantation and in leukemia. Our wok will further develop new therapies to manipulate or transfer these linked key players in immune privilege to promote allo-HSC engraftment or to overcome therapeutic resistance in leukemia.