Human B-1 and B-2 B Cells Develop from Lin-CD34+CD38lo Stem Cells

The B-1 B cell population is an important bridge between innate and adaptive immunity primarily because B-1 cells produce natural Ab. Murine B-1 and B-2 cells arise from distinct progenitors; however, in humans, in part because it has been difficult to discriminate between them phenotypically, efforts to pinpoint the developmental origins of human B-1 and B-2 cells have lagged. To characterize progenitors of human B-1 and B-2 cells, we separated cord blood and bone marrow Lin(-)CD34(+) hematopoietic stem cells into Lin(-)CD34(+)CD38(lo) and Lin(-)CD34(+)CD38(hi) populations. We found that transplanted Lin(-)CD34(+)CD38(lo) cells, but not Lin(-)CD34(+)CD38(hi) cells, generated a CD19(+) B cell population after transfer into immunodeficient NOD.Cg-Prkdc(scid) Il2rg(tm1wjl)/SxJ neonates. The emergent CD19(+) B cell population was found in spleen, bone marrow, and peritoneal cavity of humanized mice and included distinct populations displaying the B-1 or the B-2 cell phenotype. Engrafted splenic B-1 cells exhibited a mature phenotype, as evidenced by low-to-intermediate expression levels of CD24 and CD38. The engrafted B-1 cell population expressed a VH-DH-JH composition similar to cord blood B-1 cells, including frequent use of VH4-34 (8 versus 10%, respectively). Among patients with hematologic malignancies who underwent hematopoietic stem cell transplantation, B-1 cells were found in the circulation as early as 8 wk posttransplantation. Altogether, our data demonstrate that human B-1 and B-2 cells develop from a Lin(-)CD34(+)CD38(lo) stem cell population, and engrafted B-1 cells in humanized mice exhibit an Ig-usage pattern comparable to B-1 cells in cord blood.