IMGT Lexique

Transcription factors regulating B cell maturation and activation

1. B cell proliferation and differentiation of pro-B cells

Differentiation of pro-B cells results in a productive IGH V-D-J rearrangement and expression of the pre-B cell receptor (pre-BcR), composed of an Ig heavy μ chain and the surrogate light chain corresponding to the VpreB and Cλ-like (λ5 in the mouse) polypeptides. Receptor feedback inhibits further V-D-J rearrangements of IGHV genes and promotes proliferation. During this phase the surrogate light chain gene (VpreB and Cλ-like (λ5)) transcription appears to be repressed. Cessation of pre-B cell proliferation culminates in the induction of light chain gene (kappa or lambda) rearrangements and the generation of immature IgM⁺ B cells.

Immature B cells that are not reactive to autoantigens are selected and mature into antigen-responsive, resting B cells. (OCA-B/OBF-1) is a B cell specific coactivator that interacts with the POU domain transcription factors Oct1 and Oct2 which recognize the functionally essential octamer.

Upon encountering cognate antigen, a naïve B cell is stimulated to proliferate via signalling through its BcR, surface IgM (sIgM). The antigen is endocytosed, proteolytically processed, and presented to T helper (Th) cells. Extensive interactions of antigen-reactive B cells with cognate Th cells and follicular dendritic cells the result in the formation of germinal centers in secondary lymphoid tissue. Clonal proliferation of B cells in germinal centers is accompanied by differentiation involving isotype switch recombination and somatic hypermutation of Ig genes. The process culminates in the generation of memory B cells or Ig-secreting plasma cells.

2. Transcription factors regulating B cell

The transcription factors regulating B cell proliferation and differentiation can be divided into three functional groupings [1]:

factors (e.g., Aiolos, PU.1 and Spi-B) that regulate initial signalling events by the BcR perhaps by controlling the expression of key signal transduction components.
Aiolos encodes an Ikaros-related zinc finger transcription factor that is expressed at high levels in mature B cells. Aiolos^-/-B cells hyperproliferate in response to BcR engagement and also exhibit a lower threshold for activation [2]. Interestingly, reduction of Ikaros activity in T cells results in a very similar cell cycle activation phenotype as that caused by loss of Aiolos in B cells. Thus Aiolos and Ikaros appear to regulate the G0 to G1 transition as well as subsequent cell cycling. Their mechanisms of action remain to be elucidated. Spi-B is an Ets family transcription factor that is highly related to PU.1. Factors that are activated upon signalling (e.g., NF-_kB/Rel proteins that induce downstream gene expression).
factors whose expression is induced upon B cell activation (e.g., OCA-B/OBF-1 and Pip/IRF-4).
Mutation of the OCA-B gene does not result in a block to B cell development or diminished expression IgM or IgD on mature B cells. B cells can be generated even in mice that lack both OCA-B and Oct2. These results suggest that the ubiquitous transcription activator Oct1 is sufficient to promote Ig gene transcription during the antigen-dependent phase of B cell development. Although OCA-B is not essential for B cell development, it is required for immune responses against T-independent and T-dependent antigens. This appears to be caused by a failure to form germinal centers upon immunization. A molecular model for the Oct1/OCA-B/DNA complex envisages OCA-B as a molecular clamp interacting with both subdomains of the bipartite POU domain [3]. Pip/IRF-4 is a lymphoid-restricted IRF transcription factor that is recruited to composite elements within Ig light chain enhancers through a specific interaction with PU.1. Mice deficient in Pip/IRF-4 can generate normal numbers of B cells that express IgM with kappa or lambda light chains. However, these mice exhibit a dramatic reduction in serum Ig levels and do not mount detectable antibody responses to T-dependent as well as T-independent antigens. Pip is recruited to its binding site on DNA by phosphorylated PU1.

A bHLH transcription factor, ABF1, expressed in activated B lymphocytes can bind E box motifs in Ig gene enhancers either as a homodimer or as a heterodimer with E2A proteins. Expression of Id3, a negative regulator of E2A proteins, appears to selectively inhibit Ig isotype switching. E2A complexes could potentially regulate isotype switching by binding to enhancer elements at the 3' end of the IGH locus.

[1]	Glimcher, L. H. and Singh, H., Cell 96, 13-23 (1999).
[2]	Wang, J. H. et al., Immunity 9, 543-553 (1998).
[3]	Sauter, P. and Matthias, P., Mol. Cell. Biol. 18, 7397-7409 (1998).