In 1994, Turner et al. (1) reported cloning a cDNA encoding a zinc-finger–containing protein whose forced expression was sufficient to drive a cell line with an activated B cell phenotype to differentiate into plasmacytoid cells secreting Ig. At the time this was a surprising and intriguing finding, which held out the hope of unlocking the poorly understood mechanisms controlling terminal B cell differentiation. Indeed, the cloning and characterization of this protein, which Davis et al. (1) called B lymphocyte-induced maturation protein-1 (Blimp-1), not only fulfilled that hope but has also provided detailed insights into the regulation of terminal differentiation of CD4 and CD8 T cells, as well as cells in nonlymphoid lineages.

Two insightful experimental approaches provided the foundation of this classic paper. First, Turner et al. (1) modified the subtractive cloning procedure the laboratory had used 10 y earlier to clone TCR genes (2). In that study, they subtracted cDNA from B lymphocytes from cDNA isolated from T lymphocytes. In the 1994 study, they chose murine BCL1 lymphoma cells, which were known to differentiate into Ig-secreting plasmacytoid cells following treatment with IL-2 plus IL-5. They subtracted cDNA from BCL1 cells prior to cytokine treatment from cDNA isolated from cells after cytokine treatment. Having isolated 20 cDNAs specific to the differentiated cell state, they focused on Blimp-1, encoding a zinc-finger protein that was highly induced upon BCL1 cell differentiation and also highly expressed in plasmacytoma lines. Their next insightful experiment was to hypothesize and design an experiment to test the possibility that forced expression of Blimp-1, alone, would be sufficient to drive BCL1 differentiation. To avoid pitfalls of stably transformed cells, they designed an approach that at the time was novel: expressing Blimp-1 and a class II marker together in transiently transfected cells. This approach allowed transfected cells to be distinguished by flow cytometry from nontransfected cells and revealed that cells expressing Blimp-1 increased expression of Syndecan and J chain and secreted Ig. Thus, Blimp-1 had the characteristics of a “master regulator” of plasma cell development and, although their work did not show this, was likely to be a DNA-binding transcriptional regulator.

At the time of this work, it was generally accepted that transcription factors might determine lineage or developmental choices. In the context of hematopoietic cells, there was great interest in learning how transcription factors might direct pluripotent stem cells to develop into various lineages. However, no lineage-specific regulators had been identified, and combinations of transcription factors were viewed as the most likely explanation for these choices (3). In lymphocyte development, GATA-3 was known to regulate TCR gene expression (4), but the transcriptional regulators of Th1 versus Th2 differentiation were yet to be elucidated (5). Although several candidates were suggested, no B cell-specific transcription factor had been identified (6) and virtually nothing was known about gene regulation during plasma cell differentiation. MyoD, which was able to convert many differentiated cell types into muscle (7), was a well-studied transcription factor with a function most similar to that proposed for Blimp-1 by Turner et al. (1).

Soon after the Turner paper, a more detailed computer search (8) showed that Blimp-1 was, in fact, the murine homolog of PRD1-BFI (8, 9). This human cDNA was cloned by the Maniatis group based on binding of its encoded protein to the PRD1 site in the human β IFN promoter. They showed that PRD1-BFI was a negative transcriptional regulator. Recognition of this relationship immediately established Blimp-1 as a DNA-binding transcription factor, with a known binding site and with negative activity on at least some genes. Studies by the Schimpl laboratory (10) also showed that levels of Blimp-1 mRNA correlated well with Ig secretion during plasmacytic differentiation. Thus, evidence was accumulating that Blimp-1 might indeed be a master regulator of plasmacytic differentiation.

Further evidence was obtained from gene expression studies, which showed that forced expression of Blimp-1 in B cells extinguished the mature B cell program and induced gene expression patterns found in plasma cells, including expression of XBP-1, which is the direct driver of many genes required for Ig secretion (11, 12). Conditional gene ablation studies confirmed that Blimp-1 was required for plasmacytic differentiation and Ig secretion (13). Various direct targets of Blimp-1 in B cells were identified, soon allowing elucidation of the critical components of a multitiered transcriptional regulatory network leading from activated B cells to plasma cells (14).

Using the standard approach of Northern blots on RNA isolated from cell lines representing different lineages, Turner et al. (1) concluded that Blimp-1 mRNA expression was limited to plasma cells. However, once good Abs were developed, it was shown that Blimp-1 was widely expressed during murine embryonic development and was also expressed in nonlymphoid adult tissues, particularly in various epithelial cells (15). Of most interest to immunologists, Cattoretti et al. (16) showed that, although as expected, Blimp-1 was expressed in human plasma cells, it was also expressed in a subset of T cells, particularly those infiltrating tumors. Then two laboratories simultaneously reported studies from conditional gene ablation studies in T cells showing that Blimp-1 mRNA was strongly induced upon T cell activation and that it was required for normal T cell homeostasis; mice lacking Blimp-1 in T cells succumbed to spontaneous colitis (17, 18). Further studies have revealed roles for Blimp-1 in CD4 cells via modulation of IL-2–dependent activation (19), inhibition of Th1 differentiation (20), and antagonism of follicular helper T cell development (21). Several recent studies have also shown critical roles for Blimp-1 in CD8 T cell differentiation. Blimp-1 is highly expressed in and promotes the generation of short-lived effector CD8 T cells and is absent in central memory CD8 T cells (22, 23). Blimp-1 also promotes the generation of clonally exhausted CD8 cells during persistent infection (24) and is necessary for migration of T cells to peripheral locations (22). These findings will no doubt prompt further investigations into the regulatory cascades dependent on Blimp-1 in T cells.

Blimp-1 expression, coupled with the finding that embryos lacking the prdm1 gene died at about day 10 (25), showed several critical roles for Blimp-1 in embryos, including that in the development of primordial germ cells (25, 26). Subsequent studies have shown a requirement for Blimp-1 during embryonic development of several species (27). Expression in adult tissues outside of the lymphoid lineages led to the understanding that Blimp-1 plays an important role in the terminal differentiation of epidermal keratinocytes (28) and epidermal sebocytes (29). These studies have identified previously unknown gene regulation programs dependent on Blimp-1 in epithelia. A recent study shows a role for Blimp-1 in the differentiation of osteoclasts (30). Possible roles for Blimp-1 in other adult tissues showing high expression, such as retina, are currently under study and may similarly yield a new understanding of gene regulation in these lineages.

Thus, the Turner et al. (1) paper was indeed a hallmark paper, more than fulfilling its initial promise of providing insight into plasma cell differentiation. Not only did the authors develop and use innovative techniques and hypothesize the correct role of Blimp-1 in B cells, but also, by choosing the name “Blimp-1,” they provided the scientific community with the opportunity to have fun with puns (31) and pictures (32)!

Disclosures The author has no financial conflicts of interest.

Abbreviation used in this paper:

Blimp-1

B lymphocyte-induced maturation protein-1.

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