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A new wave of research recognizes a distinct subset of B regulatory cells (Breg) that maintain immune tolerance. Breg cells have been shown to exert immunoregulatory functions through the production of interleukin (IL)-10 and appear to play important roles in autoimmunity and in cancer. Despite the extensive body of evidence reinforcing the notion of B cells as potential regulatory cells, some controversy over the paucity of markers that can unequivocally identify Bregs still exists. To study the role of Breg in immune surveillance, I designed a comprehensive multi‐parameter panel of surface antibodies to define B-cell subsets in peripheral blood (PB) and cord blood (CB). The intracellular detection of IL-10 combined with flow cytometric phenotyping presented in my thesis demonstrate the presence of IL-10– producing Bregs with Treg-independent immunosuppressive functions in both the IgM memory (CD19+IgM+CD27+) and transitional (CD19+CD24hiCD38hi) PB B-cell subsets in healthy donors. The regulatory function PB Bregs against CD4+T cells and CD56+NK cells required both cell-cell contact and IL-10 production. Moreover, I demonstrate that Breg populations are expanded in the PB of AML patients and exert potent suppression of NK function mediated through 2B4-CD48 signaling. I further demonstrated the presence of IL-10- producing B cells with Treg-independent immunosuppressive properties in CB with the ability to suppress allogeneic-CD4+T cells through IL-10, as well as cell-cell contact mediated mechanisms involving CTLA-4 and CD80/CD86. I found an early and robust recovery of IL-10+B cells post-CBT. High Breg frequencies in CB may attenuate T-cell responses and contribute to the lower rates of cGVHD. My findings have important clinical implications and suggest that Bregs may be exploited to treat immune-mediated diseases. Whereas, strategies to deplete Bregs for optimal anti-cancer immunotherapy may benefit antitumor activity in AML and other cancers, adoptive transfer of donor-derived Bregs post transplant may offer a potentially effective immunomodulatory therapy for the treatment of GVHD.