Treg infusion has been drawing attention as a promising approach to control inflammatory diseases or autoimmune disorders [1,2]. Recent clinical trials of adoptive Treg transfer have yielded promising results [[3], [4], [5]]. However, the obligatory requirements to infuse high doses of donor Tregs hinders the clinical application. Therefore, it is important to identify potent Treg populations capable of effectively conveying the therapeutic effects at far lower numbers.

One of the potential target diseases for Treg transfer therapy is IBD, a debilitating chronic inflammatory condition of the gastrointestinal tract [17], inclusive of ulcerative colitis and Crohn's disease. Current treatment options for these diseases rely on immunomodulatory drugs and biological therapies, inclusive of anti-TNFα antibodies. However, drug efficacies are limited and side effects are often serious [18,19] . Given the crucial roles of Tregs in the control of IBD, Treg adoptive therapy has been tested as a potential approach to control IBD [[6], [7], [8]].

It is known that Tregs exert rigorous immune protection in several locations of stem cells: viz. testis, placenta, and hair follicle [20,21]. These tissues were demonstrated decades ago to act as immunological sanctuaries for stem cells, otherwise termed immune-privileged sites [20]. In these tissues, the immune response against stem cells is typically inhibited or prevented by multiple mechanisms, inclusive of the blood barrier, downregulation of the major histocompatibility complex molecules, cytokines, and Tregs [20]. As a result, transplanted allogeneic or xenogeneic cellular grafts survive at these sites even in the absence of exogenous immunosuppressive therapy [20,22] .

While it has remained largely unclear whether somatic stem cell niches are broadly immunosuppressive, our recent studies have demonstrated that the HSC niche within the BM is endowed with immune privilege [[9], [10], [11], [12], [13], [14], [15], [16]]. The HSC niche accommodates specialized niche-residential Treg populations characterized by high expression of an HSC marker, signaling lymphocyte activation molecule (SLAM) family member CD150 [9,10,16]. These CD150Hi BM niche Tregs express high levels of cell surface ectoenzyme CD39 and CD73, which generate extracellular adenosine, a nucleotide with powerful anti-inflammatory and immunosuppressive effects [10,16]. BM niche Treg-derived adenosine enables the persistence of allogeneic HSCs in non-conditioned immunocompetent mice, promoting engraftment [9,10,16]. In non-transplantation settings, BM niche Tregs exert pro-regenerative potentials [10]. BM niche Treg-derived extracellular adenosine protects HSCs from oxidative stress and maintains HSC quiescence, further mitigating post-irradiation BM injury [10,14]. Of note, transfer of BM niche Tregs promotes engraftment of transplanted allogeneic mismatched BMs to a greater extent than transfer of other Tregs [10]. Transfer of BM niche Tregs further rescues lethally-irradiated mice from critical BM failure [14].

However, the therapeutic utility of transferring these immune-privileged niche Tregs to the non-BM disease settings has remained untested to date. Here, we investigate the treatment efficacy of the transfer of BM niche Tregs to control the colitis using an experimental mouse model [23].