Memory B Cells without Somatic Hypermutation Are Generated from Bcl6-Deficient B Cells

Abstract

After immunization with T cell-dependent antigens, the high-affinity B cells selected in germinal centers differentiate into memory B cells or long-lived antibody-forming cells. However, a role for germinal centers in development of these B lineage cells is still controversial. We show here that Bcl6-deficient B cells, which cannot develop germinal centers, differentiated into IgM and IgG1 memory B cells in the spleen but barely differentiated into long-lived IgG1 antibody-forming cells in the bone marrow. Mutation in the V-heavy gene was null in these memory B cells. Therefore, Bcl6 and germinal center formation are essential for somatic hypermutation, and generation of memory B cells can occur independently of germinal center formation, somatic hypermutation, and Ig class switching.

In-vitro derived germinal centre B cells differentially generate memory B or plasma cells in vivo

“…It is also an intriguing fi nding that no specifi c GC microenvironment is required for B mem cell development, because the recipient mice do not develop GC. Th is result is consistent with previous fi ndings that premature B mem cells can be produced in mice in which germinal centre formation is inhibited by anti-ICOS Ab administration 56 or Bcl-6 defi ciency 27 .…”

“…IgM / D + iMB cells possessing all the same features as IgG1 + iMB cells, except for the Ig isotype, are generated at the same time as IgG1 + iMB cells, and they may correspond to the IgM + B mem cells fi rst identifi ed in the TD immune response of Bcl-6-defi cient mice 27 . In contrast, IgE + iMB cells are not generated in vivo from IgE + iGB cells.…”

“…Functionally, B mem cells can be defi ned as long-lived Ag-experienced B cells that rapidly produce Ab in response to re-challenge with soluble, adjuvant-free Ags aft er being transferred into recipient mice together with cognate Th cells 30 . Th is assay should be potentially useful to identify factors that aff ect development, longevity, in situ localization, Ag responsiveness and so on of B mem cells, but their paucity and in vitro fragility have limited these applications, except for using specifi c mutant mouse strains 27,31,32 .…”

c-Myc overexpression promotes a germinal center-like program in Burkitt's lymphoma

“…Bcl-6 is often considered the master switch of the GC reaction, as it is required for GC formation and somatic hypermutation (Toyama et al, 2002) and prevents the differentiation of GC cells to plasma cells. Bcl-6 is highly expressed in centroblasts and may be downregulated in differentiating centrocytes by NfkB-mediated processes or a strong B-cell receptor signal (Niu et al, 1998;Saito et al, 2007).…”

Nucleotide excision repair and B lymphoma: Somatic hypermutation is not the only culprit

“…Of particular importance are DNA lesions and mutations in activation-induced genes, such as AID, BCL6, FAS or toll-like receptors, which have been shown to drastically affect B-cell proliferation, survival, GC reaction and generation of memory cells, thereby leading to autoimmunity or impaired control of infections. [42][43][44][45] It is also well established that UV-induced lesions initiate systemic immune suppression and directly affect cellular and humoral immune responses, including antibody production and diversity. 37,38 Moreover, XP patients develop defective cell-mediated immunity and an impaired response to antigens, 46 suggesting a direct link between NER deficiency and immune response.…”