Cutting Edge: BLyS Enables Survival of Transitional and Mature B Cells Through Distinct Mediators

Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
The Journal of Immunology (Impact Factor: 4.92). 07/2002; 168(12):5993-6. DOI: 10.4049/jimmunol.168.12.5993
Source: PubMed


These studies characterize BLyS responsiveness and receptor expression among transitional and mature peripheral B cells. The results show a maturation-associated increase in BLyS binding capacity that reflects differential expression patterns of the three BLyS receptors. Accordingly, BLyS administration enlarges only late transitional and mature peripheral B (MB) cell compartments. Furthermore, bromodeoxyuridine labeling and cell cycle analyses show these effects are mediated through enhanced proportional survival of cells traversing the T2, T3, and MB cell stages, rather than by causing proliferation or slowing transit within these subsets. Despite similar effects on survival, BLyS up-regulates the antiapoptotic genes A1 and bcl-x(L) in MB cells but not immature B cells. Together, these findings show that, while BLyS influences B cell survival in several peripheral differentiation subsets, the downstream mediators differ, thus providing the first direct evidence for an established B lineage survival system whose intermediates change as B cells mature.

9 Reads
  • Source
    • "BAFF is the most critical soluble factor for peripheral B cell maturation and survival, and dysregulated BAFF expression is associated with lupus-like autoimmunity and B cell non-Hodgkin (B-NHL)-like lymphoma (Mackay et al., 2010; Rickert et al., 2011). BAFF-R expression is induced on newly formed B cells that are poised to egress from the bone marrow and enter the spleen, and is further upregulated as transitional B cells mature to become follicular or marginal zone (MZ) B cells (Hsu et al., 2002; Meyer-Bahlburg et al., 2008; Stadanlick et al., 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: BAFF is a soluble factor required for B cell maturation and survival. BAFF-R signals via the noncanonical NF-κB pathway regulated by the TRAF3/NIK/IKK1 axis. We show that deletion of Ikk1 during early B cell development causes a partial impairment in B cell maturation and BAFF-dependent survival, but inactivation of Ikk1 in mature B cells does not affect survival. We further show that BAFF-R employs CD19 to promote survival via phosphatidylinositol 3-kinase (PI3K), and that coinactivation of Cd19 and Ikk1 causes a profound block in B cell maturation at the transitional stage. Consistent with a role for PI3K in BAFF-R function, inactivation of PTEN mediates a partial rescue of B cell maturation and function in Baff(-/-) animals. Elevated PI3K signaling also circumvents BAFF-dependent survival in a spontaneous B cell lymphoma model. These findings indicate that the combined activities of PI3K and IKK1 drive peripheral B cell differentiation and survival in a context-dependent manner.
    Cell Reports 11/2013; 5(4). DOI:10.1016/j.celrep.2013.10.022 · 8.36 Impact Factor
  • Source
    • "• Transitional selection (Hsu et al., 2002; Crowley et al., 2008; Stohl et al., 2011) • FO, MZ survival (Lentz et al., 1996; Gross et al., 2001; Hsu et al., 2002) • GC evolution (Schiemann et al., 2001; Rahman et al., 2003; Vora et al., 2003) • TLR/BCR crosstalk, regulation? (He et al., 2010; Oropallo et al., 2011) • B-1 maintenance in spleen? "
    [Show abstract] [Hide abstract]
    ABSTRACT: B-1 and B-2 B cell populations have different progenitors, receptor diversity, anatomic location, and functions - suggesting vastly differing requisites for homeostatic regulation. There is evidence that the B lymphocyte stimulator (BLyS) family of cytokines and receptors, key factors in the homeostatic regulation of B-2 B cell subsets, is also a major player in the B-1 compartment. Here we review the development and differentiation of these two primary B cell lineages and their immune functions. We discuss evidence that BLyS or a proliferation-inducing ligand (APRIL) availability in different anatomic sites, coupled with signature BLyS receptor expression patterns on different B cell subsets, may be important for homeostatic regulation of B-1 as well as B-2 populations. Finally, we extend our working model of B cell homeostasis to integrate B-1s.
    Frontiers in Immunology 02/2013; 4:37. DOI:10.3389/fimmu.2013.00037
  • Source
    • "BAFF-deficient mice lack most mature follicular and marginal zone (MZ) B cells owing to a block at the early transitional (T1) B-cell stage, while B cell development in the BM is not affected [9] [21]. In vivo and in vitro studies have demonstrated that BAFFsignaling induces expression of anti-apoptotic molecules, confirming the significant role BAFF plays in promoting B cell survival [22] [23] [24]. BAFF-mediated B-cell survival is regulated by at least five pathways that result in attenuation of apoptosis: (1) activation of classical and alternative NF-jB; (2) activation of the anti-apoptotic proteins, "
    [Show abstract] [Hide abstract]
    ABSTRACT: Adaptive immunity depends on the production and maintenance of a pool of mature peripheral lymphocytes throughout life. The signals regulating the survival of mature splenic B cells have become a major focus in recent studies of B cell immunology. Lasting B cell persistence in the periphery is dependent on survival signals that are transduced by cell surface receptors. Cytokines have been shown to play a critical role in maintaining lymphocyte homeostasis. This review focuses on the role of cytokines and their receptors in the regulation of peripheral B cell survival, with an emphasis on those that have received relatively less attention in the literature.
    Cytokine 07/2012; 60(1):13-22. DOI:10.1016/j.cyto.2012.06.019 · 2.66 Impact Factor
Show more


9 Reads
Available from