A differentiation pathway for B1 cells in adult bone marrow

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...

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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

“…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).…”

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confidence: 99%

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

Ghosn

Sadate-Ngatchou

Yang

et al. 2011

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.

“…The B1-specified progenitors were found not only in fetal liver but also in BM of adult mice (9,24). We evaluated the B1-specified progenitors in the BM of WT and VAD mice but could not distinguish a distinct population of CD19 + B220 low/− cells in Lin − AA4.1 + gate (Fig.…”

Section: Resultsmentioning

confidence: 99%

Vitamin A-dependent transcriptional activation of the nuclear factor of activated T cells c1 (NFATc1) is critical for the development and survival of B1 cells

Maruya¹,

Suzuki²,

Fujimoto

et al. 2010

B1 cells represent a distinct subset of B cells that produce most of the natural serum IgM and much of the gut IgA and function as an important component of early immune responses to pathogens. The development of B1 cells depends on the nuclear factor of activated T cells c1 (NFATc1), a transcription factor abundantly expressed by B1 cells but not by conventional B2 cells. However, the factors that regulate the expression of NFATc1 in B1 cells remain unknown. Here we show that a vitamin A-deficient diet results in reduction of NFATc1 expression in B1 cells and almost complete loss of the B1 cell compartment. As a consequence, vitamin A-deficient mice have reduced serum IgM and are unable to mount T cell-independent antibody responses against bacterial antigens. We demonstrate that injection of all-trans retinoic acid induces the expression of NFATc1, particularly from the constitutive P2 promoter, and leads to the increase of the B1 cells. Thus, the retinoic acid-dependent pathway is critical for regulating NFATc1 expression and for maintenance of the natural memory B cell compartment.innate-like B cells | self-replenishment | natural antibodies | peritoneal-associated adipose tissues | retinoids