Some of the transcription factors that promote the differentiation of B cells into plasma cells (BLIMP1, XBP1 and interferon-regulatory factor 4, IRF4) or antagonize this developmental step in germinal-centre B cells (PAX5) have been identified. However, whether similar regulation of differentiation occurs in naive B cells is unclear. Now, a study published in The Journal of Experimental Medicine has identified the microphthalmia-associated transcription factor (MITF) as a negative regulator of plasma-cell differentiation in these cells.
Using data previously generated by microarray analysis, Lin et al. observed that Mitf cDNA was expressed by resting but not activated B cells, indicating that it could be a novel B-cell transcription factor. MITF exists as distinct isoforms that are expressed in a tissue-specific manner. These isoforms share exons 2–9 and are distinguished solely by differential first-exon usage. In this investigation, B-cell expressed MITF was shown to be encoded by the common exons and two rarely studied exons (exons 1a and 1b), and so it corresponded to a previously described isoform of MITF, MITF-A.
Mice that lack functional MITF protein — mi/mi mice — have several developmental defects, so the role of MITF specifically in B cell development was studied by transferring bone marrow from wild-type or mi/mi animals into recombination-activating gene 2-deficient hosts. B-cell development occurred normally in recipients of mi/mi bone marrow; however, these animals had increased levels of serum IgM, as well as increased numbers of splenic CD138+B220− plasma cells and IgM-secreting cells. Together with the observation that T-cell-dependent and T-cell-independent antibody responses were comparable in wild-type and mi/mi bone-marrow recipients, these results indicate that mi/mi B cells are not hyperactive as such but undergo spontaneous differentiation into plasma cells in vivo. Consistent with this, mi/mi B cells cultured in the absence of stimulation secreted increased amounts of IgM and upregulated expression of the plasma-cell marker CD138.
Further evidence of a role for MITF in suppressing plasma-cell differentiation was provided by gain-of-function studies — activated wild-type B cells retrovirally transduced to express MITF were markedly impaired in their ability to upregulate CD138 and to secrete IgM. This MITF-induced block in plasma-cell differentiation was associated with decreased levels of IRF4. Conversely, mi/mi B cells were shown to express increased levels of IRF4. The importance of these observations was demonstrated by showing that spontaneous IgM secretion by mi/mi B cells was abrogated by antisense oligonucleotide blockade of IRF4.
This study identifies MITF as a novel regulator of B-cell differentiation, which functions as a suppressor of spontaneous differentiation of naive B cells into plasma cells by inhibiting IRF4 expression. Further studies are required to define how MITF mediates IRF4 inhibition; however, as the authors were unable to detect MITF binding to the IRF4 promoter, it is likely that other transcription factors are involved.
ORIGINAL RESEARCH PAPER
Lin, L., Gerth, A. J. & Peng, S. L. Active inhibition of plasma cell development in resting B cells by microphthalmia-associated transcription factor. J. Exp. Med. 200, 115–122 (2004).
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Honey, K. MITF's calming influence. Nat Rev Immunol 4, 582 (2004). https://doi.org/10.1038/nri1419
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DOI: https://doi.org/10.1038/nri1419