Differential development of progenitor activity for three B-cell lineages.

Abstract

Cell-transfer studies presented here distinguish three murine B cell lineages: conventional B cells, which develop late and are continually replenished from progenitors in adult bone marrow; Ly-l B cells (B-la), which develop early and maintain their numbers by self-replenishment; and Ly-1 B "sister" (B-lb) cells, which share many of the properties of Ly-1 B cells, including self-replenishment and feedback regulation of development but can also readily develop from progenitors in adult bone marrow. The sequential emergence of these lineages, the time at which their progenitors function during ontogeny, and the distinctions among their repertoires and functions suggest that evolution has created a layered immune system in which-the immune response potential ofeach successive lineage is adapted to its particular niche. (5) and B-cell neoplasms (6). They tend to use a restricted set of variable-region (V) genes (7-10) and to use N-region insertions less often than conventional B cells (11). These repertoire differences may arise from differences in the diversity-generating mechanisms in individual lineages (12), to the different times that lineages develop (3), and/or to selection by particular antigens (13)(14)(15)(16) (17).In this study, we characterize the progenitor capacity of FL and adult bone marrow (BM) for three kinds of mature B We show here that significant progenitor activity for B-lb cells is present in fetal and adult animals, whereas progenitor activity for B-la cells is readily detectable in FL but is largely missing or nonfunctional in adult BM. We further show (i) that the failure to detect progenitor activity for B-la cells in adult BM is not due to the presence of inhibitors or the absence of inducers that regulate B-la development, (ii) that the progenitors for conventional B cells are already distinct from progenitors for the B-1 subsets in 14-day FL, and (iii) that the distinctive development of the three B-cell populations depends on properties inherent in their progenitors and cannot be explained solely by differential selection.Taken together, these studies indicate that B-ia and B-lb cells belong to separate developmental lineages and that both lineages are distinct from the conventional B lineage. We discuss these findings in the context of our recent hypothesis that these B-cell lineages reflect the existence of an evolutionarily layered immune system in which the immune response potential of each successive lineage is adapted to particular challenges (22). MATERIALS AND METHODS

Major histocompatibility complex class II expression distinguishes two distinct B cell developmental pathways during ontogeny.

“…Our results support the concept of (at least) two developmentally and functionally distinct B cell lineages within the immune system (10,(30)(31)(32): one generated during fetal life and one in the adulthood which begins to emerge after birth. Developmentally, it has been shown that embryonic (33), fetal omentum (34), and fetal liver (9, 35) B cell progenitors preferentially give rise to B-la (CD5 +) B cells.…”

“…Developmentally, it has been shown that embryonic (33), fetal omentum (34), and fetal liver (9, 35) B cell progenitors preferentially give rise to B-la (CD5 +) B cells. Given our earlier studies (10) and those of Hardy and Hayakawa (9), it is reasonable to assume that the B-la (and possibly B-lb) lineage(s) are a part of what we have defined here as the FT developmental pathway. As expected, sorted I-A-pre-B cells from young spleens can give rise to CD5 + B ceils in FLST2 cultures (Lain, K.-P., and A. M. Stall, manuscript in preparation).…”

“…The lack of TdT expression results in a lack of N region additions in the fetal mouse Ig V-D-J junctional sequences as compared with those derived from the adult BM (7,8). More significantly, recent studies (9,10) show that fetal liver but not adult BM pro-B cells readily reconstitute CD5 + B cells, strongly suggesting that there are intrinsic developmental differences in the B cell progenitors obtained at distinct time points during ontogeny. However, to date, no phenotypic cell surface markers have been identified which can distinguish between fetal liver and adult BM-derived progenitor cells.…”

Peritoneal B‐2 cells comprise a distinct B‐2 cell population with B‐1b‐like characteristics

“…Thus, over time, peritoneal B-2 cells acquired characteristics of B-1b, not B-1a, B cells. Previous work has shown that B-1b cells can develop from bone marrow progenitors in the adult, whereas B-1a cells do not or do so at a vanishingly small rate [33]. The apparent transition of peritoneal B-2 cells toward a B-1b-like phenotype is consistent with the derivation of B-1b cells from the bone marrow.…”

IL-15 and IL-15 Receptor Selectively Regulate Differentiation of Common Mucosal Immune System-Independent B-1 Cells for IgA Responses

“…To separate B cell subsets to B-1 and B-2 cells (17,19), lymphocytes from different tissues were incubated with FITC-conjugated anti-IgD (PharMingen, 11-26c.2a) and PE-conjugated anti-IgM (IgH-6 b ; PharMingen, AF6-78) for the IL-15-induced B cell-proliferation assay. FITC-conjugated anti-IgA (PharMingen, R5-140), PE-conjugated anti-CD45R/B220 (PharMingen, RA3-6B2), and biotinylated anti-IgM (PharMingen, AF6-78) followed by streptavidin-conjugated PerCP (Becton Dickinson, Sunnyvale, CA) were used for the separation of sIgM ϩ sIgA Ϫ or sIgA ϩ B-1 and B-2 cells for the analysis of IL-15R and C␣ expressions and IgA production (14, 16, 17, 28 -30).…”