Terminal differentiation of lymphocytes depends on Blimp-1
Introduction
Terminal differentiation is a generally irreversible process that leads to the acquisition of effector function and often to exit from the cell cycle. During an immune reaction, mature B and T lymphocytes can differentiate into effector cells that have diverse functions, enabling them to eradicate pathogens and infected cells as well as to set aside cells for the maintenance of immunological memory. Although the terminal differentiation program of B cells into antibody-producing plasma cells is well defined and characterized, the late stages of T-cell differentiation into the various subsets of memory and effector T cells is less understood. In this review we will highlight recent studies regarding the function of B lymphocyte induced maturation protein 1 (Blimp-1) in the adaptive immune system that have raised the prospect that the terminal differentiation of the lymphocyte lineages might be more similar than previously expected.
Section snippets
Blimp-1 in plasma cell differentiation
Mouse Blimp-1 [1] and its human orthologue, PRDI-BF1 [2], have long been implicated in the differentiation of B cells into plasma cells. Within the B-cell lineage, Blimp-1 is specifically expressed in all antibody-secreting cells (ASCs) including plasma cells and plasmablasts [3, 4, 5]. Enforced expression of Blimp-1 is sufficient to drive mature B cells towards the ASC fate [6, 7], whereas gene-knockout studies have demonstrated that Blimp-1 is also required for the formation of plasma cells [8
Blimp-1 regulates T-cell homeostasis
An unexpected outcome of the studies performed on the Blimp-1-mutant mice was the finding that Blimp-1 plays a crucial role in controlling T-cell homeostasis [41••, 42••]. Mice that had a T cell specific deletion or those reconstituted with Blimp-1-mutant foetal liver both showed a severely altered T-cell compartment with markedly increased numbers of effector-memory cells and T cell-mediated immune pathology. Using Blimp-1–GFP, we have shown that Blimp-1 is expressed in a subset of
Inactivation of Blimp-1 in B-cell lymphoma
Although many studies have demonstrated that Blimp-1 is expressed in myeloma cells, a surprising new function for Blimp-1 as a tumour suppressor was recently revealed. In two independent studies, the human PRDM1 gene was found to be commonly mutated in diffuse large B cell lymphoma (DLBCL) — the most frequent type of adult non-Hodgkin lymphoma [46••, 47••]. Interestingly, the PRDM1 mutations were restricted to those lymphomas that have an activated B-cell phenotype (ABC-DLBCL) that resembled
Conclusions
There is now a wealth of data that demonstrates that Blimp-1 functions as a lynchpin in the regulatory network that drives terminal lymphocyte differentiation. In the B-cell lineage, this involves several other key transcription factors such as Bcl-6 and Pax5, which promote the B-cell state, and IRF-4 and XBP-1, which favour differentiation. This mutual antagonism ensures that these key developmental stages in B-cell differentiation are kept transcriptionally distinct. As Blimp-1 is involved in
Update
The model of Blimp-1-mediated plasma cell differentiation presented here has received recent support from an immunohistochemical study of transcription factor expression in the mouse and human germinal centres [48]. This study found that, whereas the majority of B cells co-express Pax5, Bcl6 and low levels of IRF4, some germinal centre centrocytes co-express Blimp-1, IRF4 and Pax5 and therefore could represent the in vivo equivalent of the pre-plasmablast population depicted in Figure 1.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We would like to thank members of the Walter and Eliza Hall Institute B-cell program for discussions as well as Sebastian Carotta and Kylie Greig for critical comments on the manuscript. This research was supported by the Leukaemia Foundation of Australia (AK), the Pfizer Australia Research Fellowship (SLN) and the National Health and Medical Research Council of Australia.
References (51)
- et al.
Blimp-1, a novel zinc finger-containing protein that can drive the maturation of B lymphocytes into immunoglobulin-secreting cells
Cell
(1994) - et al.
Blimp-1 is required for the formation of immunoglobulin secreting plasma cells and pre-plasma memory B cells
Immunity
(2003) - et al.
Blimp1 defines a progenitor population that governs cellular input to the sebaceous gland
Cell
(2006) - et al.
Blimp-1 orchestrates plasma cell differentiation by extinguishing the mature B cell gene expression program
Immunity
(2002) - et al.
XBP1, downstream of Blimp-1, expands the secretory apparatus and other organelles, and increases protein synthesis in plasma cell differentiation
Immunity
(2004) - et al.
Loss of Pax5 promotes plasma cell differentiation
Immunity
(2006) - et al.
Transcription factor IRF4 controls plasma cell differentiation and class-switch recombination
Nat Immunol
(2006) - et al.
Differential effect of B lymphocyte-induced maturation protein (Blimp-1) expression on cell fate during B cell development
J Exp Med
(1998) - et al.
Identification and characterization of a novel repressor of beta-interferon gene expression
Genes Dev
(1991) - et al.
Commitment of B lymphocytes to a plasma cell fate is associated with Blimp-1 expression in vivo
J Immunol
(2000)
PRDM1/Blimp-1 is expressed in human B-lymphocytes committed to the plasma cell lineage
J Pathol
Plasma cell ontogeny defined by quantitative changes in blimp-1 expression
J Exp Med
Blimp-1 overcomes the block in IgM secretion in lipopolysaccharide/anti-mu F(ab′)2-co-stimulated B lymphocytes
Eur J Immunol
BLIMP-I mediates extinction of major histocompatibility class II transactivator expression in plasma cells
Nat Immunol
Blimp1 is a critical determinant of the germ cell lineage in mice
Nature
The zinc finger transcriptional repressor Blimp1/Prdm1 is dispensable for early axis formation but is required for specification of primordial germ cells in the mouse
Development
Prdm1 acts downstream of a sequential RA, Wnt and Fgf signaling cascade during zebrafish forelimb induction
Development
The B-cell maturation factor Blimp-1 specifies vertebrate slow-twitch muscle fiber identity in response to Hedgehog signaling
Nat Genet
Modular nature of Blimp-1 in the regulation of gene expression during B cell maturation
J Immunol
Transcriptional repression by blimp-1 (PRDI-BF1) involves recruitment of histone deacetylase
Mol Cell Biol
PRDI-BF1 recruits the histone H3 methyltransferase G9a in transcriptional silencing
Nat Immunol
Blimp1 associates with Prmt5 and directs histone arginine methylation in mouse germ cells
Nat Cell Biol
PRDI-BF1/Blimp-1 repression is mediated by corepressors of the Groucho family of proteins
Genes Dev
Repression of c-myc transcription by Blimp-1, an inducer of terminal B cell differentiation
Science
Blimp-1-dependent repression of Pax-5 is required for differentiation of B cells to immunoglobulin M-secreting plasma cells
Mol Cell Biol
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2018, Molecular ImmunologyCitation Excerpt :B lymphocyte-induced maturation protein 1 (Blimp-1) has been termed the ‘master regulator’ in plasma cell differentiation (Shapiro-Shelef et al., 2003). It is however also expressed in other non B cell lineages such as macrophages, epithelial cells and in particular, T cells (Minnich et al., 2016; Nutt et al., 2008; Xin et al., 2016; Kallies and Nutt, 2007). Several groups report that mice lacking Blimp-1 in its T cell lineage had an increased level of peripheral effector CD4+ and CD8+ T cells (Nutt et al., 2007; Kallies et al., 2006; Martins et al., 2006).