Phenotypically distinct B cell development pathways map to the three B cell lineages in the mouse

B-1 B cells have been proposed to be preferentially generated from fetal progenitors, but this view is challenged by studies concluding that B-1 production is sustained throughout adult life. To address this controversy, we compared the efficiency with which hematopoietic stem cells (HSCs) and common lymphoid progenitors (CLPs) from neonates and adults generated B-1 cells in vivo and developed a clonal in vitro assay to quantify B-1 progenitor production from CLPs. Adult HSCs and CLPs generated fewer B-1 cells in vivo compared with their neonatal counterparts, a finding corroborated by the clonal studies that showed that the CLP compartment includes B-1-and B-2-specified subpopulations and that the former cells decrease in number after birth. Together, these data indicate that B-1 lymphopoiesis is not sustained at constant levels throughout life and define a heretofore unappreciated developmental heterogeneity within the CLP compartment.bone marrow | clonal analysis | hematopoiesis I mmune system development has been hypothesized to be a layered process in which lymphoid populations of increased complexity are produced in successive waves in the fetus, neonate, and adult. The initial wave of fetal lymphopoiesis has been proposed to generate lymphocytes involved in innate immunity, whereas waves appearing later produce cells involved in adaptive immune responses (1). A corollary of the layered immune system hypothesis is that, after peaking in the fetus/neonate, the initial wave(s) of lymphopoiesis wanes as the adult wave establishes.The layered immune system hypothesis arose from studies aimed at defining the origin of two types of B lymphocytes, termed B-1 and B-2 cells (2). B-1 cells are innate effectors distinguished by their preferential localization in serous cavities and an unusual sIgM high CD11b + CD5 + B-1a and sIgM high CD11b + CD5 − B-1b phenotype (3, 4). B-1a cells spontaneously secrete IgM natural antibodies, whereas production of Ig by B-1b cells can be induced by antigen exposure, and the latter cells exhibit immunologic memory (5, 6). Human B-1 cells with properties similar to those described in mice have recently been described (7). In contrast, conventional B cells, referred to as B-2 cells, are mediators of adaptive immune responses, predominate in the spleen and lymph nodes, and undergo somatic hypermutation after antigen encounter (8, 9).Studies showing that cells from fetal liver are more efficient than cells from adult bone marrow at reconstituting B-1 cells in irradiated recipients initially suggested that innate B cells arise from progenitors that appear during a fetal wave of development (10, 11). CD5 + B-1a cells, in particular, were preferentially generated from fetal sources (2, 12, 13). These early findings are supported by more recent studies showing the existence of lineage negative (Lin − ) CD45R −/low CD19 + B-1-specified progenitors that arise in the embryonic yolk sac, peak in number in the fetal liver, and then decline in the adult (14-17). Taken together with data showing th...

supporting

confidence: 75%

“…S1). We also examined the CLP compartment for determinants that would segregate B-1-specified CLPs, like CD138 (17), CD11b (Mac-1) (35), and MHC class II antigens (17,36). However, neither CD138 nor CD11b selectively identified B-1-or B-2-specified CLPs (Figs.…”

Section: Discussionmentioning

confidence: 99%

Reduced production of B-1–specified common lymphoid progenitors results in diminished potential of adult marrow to generate B-1 cells

Barber

Montecino‐Rodriguez

Dorshkind

2011

“…For cell transfer studies, PerC cells were harvested in deficient RPMI medium 1640 without serum as described in ref. 24. For FACS staining, PerC and spleen cells were harvested in serum-containing medium.…”

Section: Methodsmentioning

confidence: 99%

Division and differentiation of natural antibody-producing cells in mouse spleen

Yang

Tung

Ghosn

et al. 2007

Self Cite

156

137

B-1a cells reside in both the peritoneal cavity and the spleen. LPS stimulates splenic B-1a to differentiate to plasma cells producing natural IgM specific for microbial and self antigens. However, there are conflicting views as to whether the B-1a cells divide before this differentiation occurs, and hence how the resident B-1a population is maintained in the spleen. Studies here resolve this dispute in favor of both sides: we show that (some or all) B-1a cells resident in the spleen respond to LPS by differentiating to plasma cells immediately, without dividing; however, we also show that additional B-1a cells immigrate into the spleen after LPS stimulation and divide at least once before differentiating. Importantly, the studies we presently describe reveal the complex cell migration and differentiation events that collectively underlie the rapid production of natural antibodies in response to in vivo LPS stimulation. Thus, the studies present a different view of the roles that B-1a cells play in the early phases of the innate immune response.B-1 ͉ CD138 ͉ CD5 ͉ lipopolysaccharide ͉ plasma cells

“…These findings, which provided some of the earliest evidence of lineage distinctions between B-1 and B-2 cells, also showed that some B-1 progenitors persist in adults. However, discussions of whether the BM-derived B-1 cells arose from independent progenitors or from developmental diversion of B-2 cells pushed the entire issue into the realm of experts, from whence it has only now been rescued by the recognition of distinct embryonic progenitors for B-1 and B-2 (1) and of a small subset of phenotypically distinct B-1 progenitors in adult BM (7)(8)(9).…”

mentioning

confidence: 99%

Distinct progenitors for B-1 and B-2 cells are present in adult mouse spleen

Ghosn

Sadate-Ngatchou

Yang

et al. 2011

Self Cite

Recent studies by Dorshkind, Yoder, and colleagues show that embryonic (E9) B-cell progenitors located in the yolk sac and intraembryonic hemogenic endothelium before the initiation of circulation give rise to B-1 and marginal zone B cells but do not give rise to B-2 cells. In studies here, we confirm and extend these findings by showing that distinct progenitors for B-1 and B-2 cells are present in the adult spleen. Furthermore, we show that the splenic B-cell progenitor population (lin -CD19 + /B220 lo/− /CD43 -) that gives rise to B-1 cells is likely to be heterogeneous because, in some recipients, it also gives rise to B cells expressing the marginal zone phenotype (B220 hi IgM hi IgD lo CD21 hi ) and to some (CD19 -CD5 hi ) T cells. In addition to the well-known function differences between B-1 and B-2, our studies demonstrate that substantial developmental differences separate these B-cell lineages. Thus, consistent with the known dependence of B-2 development on IL-7, all B-2 progenitors express IL-7R. However, >30% of the B-1 progenitors do not express this marker, enabling the known IL-7 independent development of B-1 cells in IL-7 −/− mice. In addition, marker expression on cells in the early stages of the B-2 development pathway (CD19 -/c-Kit lo/− / Sca-1 lo/− ) in adult bone marrow distinguish it from the early stages of B-1 development (CD19 hi /c-Kit + /Sca-1 + ), which occur constitutively in neonates. In adults, in vivo inflammatory stimulation (LPS) triggers B-1 progenitors in spleen to expand and initiate development along this B-1 developmental pathway. A fter many years of smoke but no clear fire, Dorshkind, Yoder, and colleagues (1) finally identified embryonic (E9) B-cell progenitors that give rise to B-1 and marginal zone (MZ) B cells in adoptive recipients, but do not give rise to B-2 cells. Located in the yolk sac and intraembryonic hemogenic endothelium before the initiation of circulation, these B-1 and MZ B progenitors predate the emergence of the well-known B-cell progenitors in the fetal liver, which collectively give rise to B-1, B-2, and MZ B cells (1-3). The fetal liver B-cell progenitors are detectable in the fetus from day 13 onwards. These progenitors start to give rise to mature IgM-bearing B cells shortly before birth and collectively continue to populate the B-cell compartments during neonatal life and beyond.