Abstract
The Oct2 protein, encoded by the Pou2f2 gene, was originally predicted to act as a DNA binding transcriptional activator of immunoglobulin (Ig) in B lineage cells. This prediction flowed from the earlier observation that an 8-bp sequence, the “octamer motif,” was a highly conserved component of most Ig gene promoters and enhancers, and evidence from over-expression and reporter assays confirmed Oct2-mediated, octamer-dependent gene expression. Complexity was added to the story when Oct1, an independently encoded protein, ubiquitously expressed from the Pou2f1 gene, was characterized and found to bind to the octamer motif with almost identical specificity, and later, when the co-activator Obf1 (OCA-B, Bob.1), encoded by the Pou2af1 gene, was cloned. Obf1 joins Oct2 (and Oct1) on the DNA of a subset of octamer motifs to enhance their transactivation strength. While these proteins variously carried the mantle of determinants of Ig gene expression in B cells for many years, such a role has not been borne out for them by characterization of mice lacking functional copies of the genes, either as single or as compound mutants. Instead, we and others have shown that Oct2 and Obf1 are required for B cells to mature fully in vivo, for B cells to respond to the T cell cytokines IL5 and IL4, and for B cells to produce IL6 normally during a T cell dependent immune response. We show here that Oct2 affects Syk gene expression, thus influencing B cell receptor signaling, and that Oct2 loss blocks Slamf1 expression in vivo as a result of incomplete B cell maturation. Upon IL4 signaling, Stat6 up-regulates Obf1, indirectly via Xbp1, to enable plasma cell differentiation. Thus, Oct2 and Obf1 enable B cells to respond normally to antigen receptor signals, to express surface receptors that mediate physical interaction with T cells, or to produce and respond to cytokines that are critical drivers of B cell and T cell differentiation during a humoral immune response.
Highlights
Octamer binding protein 2, or Oct2, is encoded by the Pou2f2 gene
We have shown, using the same quantitative tools that identified the role of Oct2 and IL5 in antibody-secreting cell (ASC) differentiation, that Obf1 is required for T cell dependent ASC differentiation, but not isotype switching, both in vitro and in vivo [29]
We propose that Oct2 regulates Syk gene expression to enable positive selection through the B cell receptor (BCR) and entrance to the mature follicular B cell pool, and it may enable differentiation of B1 and marginal zone (MZ) B cells, which are highly dependent on BCR signal strength
Summary
Octamer binding protein 2, or Oct, is encoded by the Pou2f2 gene. It was one of the first cell type-specific transcription factors identified and cloned [1]. We have shown, using the same quantitative tools that identified the role of Oct and IL5 in ASC differentiation, that Obf is required for T cell dependent ASC differentiation, but not isotype switching, both in vitro and in vivo [29] In addition to these established roles for Oct and Obf in B cells, we include below data from studies on other genes that we have found to be differentially regulated in Oct2- and Obf1deficient B cells. These include the genes encoding the Syk protein, which is an important transducer of BCR signals and Slamf, an essential mediator of cell:cell contact, especially in the context of a developing GC. We include these data to add to our understanding of the valuable roles that Oct and Obf play in B cell responses to antigen and to T cell help
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