The LRF transcription factor regulates mature B cell development and the germinal center response in mice

Abstract

IntroductionHSCs give rise to immature B cells in the BM, which subsequently migrate to the secondary lymphoid organs, such as the LNs and spleen. The vast majority of newly formed BM B cells die at the transitional B cell stage during the following few days and fail to enter the long-lived mature B cell pool, which mainly consists of B1, follicular B (FOB), and marginal zone B (MZB) cells in the secondary lymphoid organs. During B cell maturation, signals driven by cell-surface receptors and downstream transcription factors must be regulated in a coordinated fashion to maintain mature B cell homeostasis. In particular, both B cell antigen receptor (BCR) and BAFF, the B cell-activating factor belonging to the TNF family, relay crucial signals for mature B cell development and survival, while the Notch pathway regulates MZB cell development (1-5).B cells are indispensable for humoral immunity, as they ultimately give rise to antibody-secreting plasma cells. During T celldependent (TD) antibody responses, naive B cells form germinal centers (GCs), a distinct histologic structure found in secondary lymphoid organs. Naive B cells become activated upon interaction with T cells and antigen-presenting cells and begin to rapidly proliferate and form the characteristic GC structure, in which 2 major genetic changes occur: somatic hypermutation (SHM) and class switch recombination (CSR). SHM modifies the affinity of the BCR for the cognate antigen by introducing predominantly point mutations into the variable region of Ig genes, while CSR replaces the constant regions of the Ig heavy (IgH) chain with those of other isotypes and allows the expression of antibodies that have the same antigen specificity but are different secondary IgH isotypes.

LRF-mediated Dll4 repression in erythroblasts is necessary for hematopoietic stem cell maintenance

“…8 Furthermore, despite its critical role in the B versus T-lymphoid lineage fate determination, Lrf is dispensable for maintenance of "committed" BM B cells, as early B-cell development in the BM is grossly normal when the Lrf gene is inactivated at the pro-B cell stage. 9 In this study, we asked how HSC self-renewal and lymphoid differentiation is balanced in the context of Notch signaling in adult BM. We show that Notch1/Dll4-mediated T-cell instructive signals to LT-HSCs are suppressed by Lrf expression in the BM microenvironment.…”

The BTB-ZF transcription factors

“…43,44 Neither IL-4 nor STAT6 LRF is important beyond the T/B lineage split, with B cell-specific deletion of Zbtb7a resulting in the generation of more marginal zone B cells but fewer follicular and germinal center B cells. 93 The embryonic lethality of LRF-deficient mice is also associated with profound anemia. 32,92 GATA1, a key transcriptional regulator of erythropoiesis, was found to activate the expression of Zbtb7a, which, in turn, suppressed expression of the gene encoding the proapoptotic protein Bim.…”

Role of LRF/Pokemon in lineage fate decisions

“…The tumor suppressor p19Arf, a transcriptional target of LRF, 21 was significantly upregulated in LRF-deficient GC B-cells, and de-repression of the p19Arf gene accounts for, at least in part, the impaired proliferation and increased apoptosis seen in LRF-deficient GC B-cells. 40 Notably, despite its critical role in lymphoid lineage fate determination at the HSC/progenitor stages, LRF was found to be dispensable to the maintenance of immature B cells in the bone marrow of Lrf Flox/Flox ;Mb1-Cre mice. These findings were also consistent with the fact that treatment with g secretase inhibitor restored normal B-cell development in Lrf Cell fate determination by positional cues is a fundamental mechanism in animal and plant development.…”

“…Finally, LRF is also highly expressed in GC B-cells and nonHodgkin lymphoma tissues, 21,40 implying that LRF may also function in GC formation and lymphomagenesis, as does BCL6. Indeed, GC-B cells are dramatically reduced in B-cell-specific Lrf conditional knockout mice (Lrf Flox/Flox ;Mb1-Cre) after immunization with T-cell-dependent antigens.…”

“…Indeed, GC-B cells are dramatically reduced in B-cell-specific Lrf conditional knockout mice (Lrf Flox/Flox ;Mb1-Cre) after immunization with T-cell-dependent antigens. 40 Although Bcl6 knockout For personal use only. on May 12, 2018.…”