New insights into the regulation of human B-cell differentiation

Abstract

B lymphocytes provide the cellular basis of the humoral immune response. All stages of this process, from B-cell activation to formation of germinal centers and differentiation into memory B cells or plasma cells, are influenced by extrinsic signals and controlled by transcriptional regulation. Compared to naïve B cells, memory B cells display a distinct expression profile, which allows for their rapid secondary responses. Indisputably, many B-cell malignancies result from aberrations in the circuitry controlling B-cell function, particularly during the germinal centre (GC) reaction. Here, we review new insights into memory B-cell subtypes, recent literature on transcription factors regulating human B-cell differentiation and further evidence for B-cell lymphomagenesis emanating from errors during GC cell reactions.

Figure 1. Characteristics and factors among mature human naïve and memory B cell subsets

Naïve B cells are identified as IgM⁺IgD⁺cells, which possess no somatic hypermutations (SHMs) and little capacity to proliferate or differentiate into antibody secreting cells (ASCs), likely due to intrinsic differences in expression of factors involved in quiescence including Kruppel-like factors (KLF)4, KLF9 and promyelocytic leukemia zinc finger (PZLF) [10]. IgM⁺IgD⁺CD27⁺ memory B cells probably form the human counterparts of murine splenic marginal zone B cells, exhibit SHMs and require Notch2 for their development [23]. Classical switched CD27⁺ memory B cells readily proliferate and differentiate into ASCs upon stimulation and are maintained through expression of anti-apoptotic Bcl-2 family members [11]. Fc-receptor-like 4 (FCRL4) is expressed on a subset of primarily CD27⁻ memory B cells [25,26] that resides in epithelial tissue-based niches and shows a distinct expression profile. *The proliferation of FCRL4⁺ B cells is only high in response to CD40L and cytokines, they fail to proliferate in response either to BCR ligation or Staphylococcusaureus stimulation. 2° lymphoid, secondary lymphoid organs; PB, peripheral blood; MALT, mucosa-associated lymphoid tissue. Factors for which protein levels have been assessed are indicated in regular font, whereas italics indicates that only transcription has been detected. Functions of factors are indicated in parentheses.

Figure 2. The ‘checks and balances’ system of human PC differentiation

T-cell dependent (TD) activation of Ag-specific B cells leads to formation of germinal centers (GCs) in lymphoid organs. Several transcription factors are maintained or upregulated in GC B cells to allow affinity maturation to take place, i.e. inhibiting the differentiation of GC B cells into PCs by direct repression of the transcription of factors that are required for PC formation [29,30]. Consequently, expression levels of these repressors must decrease to allow the differentiation of GC B cells once B cell selection is successfully achieved. Once expressed, PC factors repress the factors required for B cell identity and GC phenotype. Also, PC factors can induced their own and each others expression, in order to fully establish the PC phenotype. Research with human B cell systems has confirmed and extended the factors involved in the GC repression network established in murine studies. In the figure, protein expression and repression mechanism that are confirmed or discovered in human systems are displayed in black, results from mouse studies only are displayed in grey. For human B cells it was shown that BCL6 is highly expressed in GC center B cells [5] and represses BLIMP1 [39] as well as STAT3 [41]. PAX-5 and Spi-B are expressed in naïve, memory and activated human B cells [5,42] and repress BLIMP1 and XBP-1 in activated GC B cells [42,49]. BLIMP1 and IRF-4 levels are high in human plasmablasts and PCs [5,37]. IL-21 secreted by Tfh induces BLIMP1 in a STAT3-dependent manner [33]. BCR Ag stimulation induces phosphorylation and degradation of BCL6 [107], while CD40 triggering results in downregulation of BCL6 expression [108], suggesting a role for Ag and T cell help in GC differentiation by modulating BCL6 levels. CD25⁺ GC B cells express high levels of pSTAT5, a direct inducer of BCL6, resulting in memory differentiation [39]. BCL6 may or may not be required for the differentiation of memory B cells in the GC [60].