PR domain zinc finger protein 1, or B lymphocyte-induced maturation protein-1 (BLIMP-1), is a
protein in humans encoded by the gene PRDM1 located on chromosome 6q21.[5] BLIMP-1 is considered a 'master regulator' of
hematopoietic stem cells, and plays a critical role in the development of
plasma B cells,
T cells,
dendritic cells (DCs),
macrophages, and
osteoclasts.
Pattern Recognition Receptors (PRRs) can activate BLIMP-1, both as a direct target and through downstream activation.[6][7][8] BLIMP-1 is a transcription factor that triggers expression of many downstream signaling cascades.[6][9][10][11] As a fine-tuned and contextual rheostat of the immune system, BLIMP-1 up- or down-regulates immune responses depending on the precise scenarios.[6][10][12] BLIMP-1 is highly expressed in
exhausted T-cells – clones of dysfunctional T-cells with diminished functions due to chronic immune response against cancer, viral infections, or organ transplant.[7][8][13][14]
Function
As a potent repressor of
beta-interferon (IFN-β), BLIMP-1 competes for interferon regulatory factors (IRF) binding sites in the IFN-β promoter due to its sequence similarity with
IRF1 and IRF2.[6][9] However, BLIMP-1 cools down and activates immune responses in a highly contextual manner. BLIMP-1 represses
NFκB/
TNF-R pathway repressor
NLRP12, thus indirectly activating the immune response.[6] BLIMP-1 expression is also upregulated by danger signals from double-stranded RNA (specific to virus),
lipopolysaccharides (specific to
gram-negative bacteria),
unmethylated CpG DNA (abundant in bacterial genomes), and cancer inflammation via
Toll-like receptor (TLR) 3,
TLR-4,
TLR-9, and
STAT signaling, respectively.[6][9]
The increased expression of the BLIMP-1 protein in
B lymphocytes,
T lymphocytes,
NK cells and other immune system cells leads to an immune response through proliferation and differentiation of antibody secreting
plasma cells. In a monocytic cell line, over-expression of BLIMP-1 can lead to differentiation into mature
macrophages. BLIMP-1 also plays a role in
osteoclastogenesis as well as in the modulation of
dendritic cells. Other cells of the immune system such as human peripheral blood
monocytes and
granulocytes also express BLIMP-1.[6][10][11]
As a transcriptional
repressor, BLIMP-1 has a critical role in the foundation of the mouse
germ cell lineage, as its disruption causes a block early in the process of primordial germ cell formation. BLIMP-1-deficient mutant embryos form a tight cluster of about 20 primordial germ cell-like cells, which fail to show the characteristic migration, proliferation and consistent repression of
homeobox genes that normally accompany specification of primordial germ cells. BLIMP-1 is widely expressed in
stem cells of developing embryos.[6] The genetic lineage-tracing experiments indicate that the BLIMP-1-positive cells originating from the proximal posterior
epiblast cells are indeed the lineage-restricted primordial germ cell precursors.[15]
B cell development
BLIMP-1 is an important regulator of plasma cell differentiation. During B cell development, a B cell can either differentiate into a short-lived plasma cell or into a germinal center B cell after receiving proper activation and co-stimulation.[6][10] BLIMP-1 acts as a master gene regulating the transcriptional network that regulates B cell terminal differentiation. Except for
naïve and
memory B cells, all antibody secreting cells express BLIMP-1 regardless of their location and differentiation history.[5] BLIMP-1 directly initiates
unfolded protein response (UPR) by activating Ire1,
Xbp1, and
Arf6, allowing the
plasma B cells to produce vast amounts of antibody.[6][12] BLIMP-1 expression is carefully controlled: the expression of BLIMP-1 is low or undetectable in primary B cells, and only upregulated in plasmablasts and plasma cells.[16] BLIMP-1 is a direct transcriptional target of IRF-4, which is also necessary for B-cell differentiation.[6] The premature expression of BLIMP-1 in primary B cells results in cell death, so only cells that are ready to initiate transcription driven by BLIMP-1 are able to survive and differentiate.[5][13] However, without BLIMP-1, proliferating B cells are unable to differentiate to plasma cells, resulting in severe reduction in production of all isotypes of
immunoglobulin.[5]
T cell development
BLIMP-1 promotes naive T-cells to differentiate into T-helper (Th) 2 lineage, while repressing the differentiation into Th1, Th17, and follicular Th.[9] BLIMP-1 is also required for differentiation of
cytotoxic T-cell.[13] Specifically, the expression of
granzyme B (a source of cytotoxicity) in Tc depends on the presence of BLIMP-1 and interleukin-2 (
IL-2) cytokine.[6][9]
BLIMP-1 is a gatekeeper of T-cell activation and plays a key role in maintaining normal T cell
homeostasis. BLIMP-1 deficiency leads to high numbers of activated T helper cells and severe autoimmune diseases in laboratory mice.[13] BLIMP-1 is important in dampening autoimmunity, as well as antiviral and antitumor responses.[13] BLIMP-1 regulates T cell activation through a negative feedback loop: T cell activation leads to IL-2 production, IL-2 leads to PRDM1 transcription, and BLIMP-1 feeds back to repress IL-2 gene transcription.[5]
T cell exhaustion
Multiple studies have reported high expression of BLIMP-1 in
exhausted T cells.[13][14] T cell exhaustion is usually a result of chronic immune activations, commonly caused by viral infection (e.g. HIV), cancer, or organ transplant.[7][13][14] High expression of BLIMP-1 in Tc and Th cells is associated with the transcription of receptors inhibiting immune responses, though it is unclear whether the relation between BLIMP-1 expression and T-cell exhaustion is causal or just associative.[8]
BLIMP-1 helps the production of short-lived effector T cells and clonally exhausted T cells. It also helps with the migration of T cells out of the spleen and lymph nodes into peripheral tissues. However, BLIMP-1 does not promote the production of long-lived effector memory cells. BLIMP-1 allows the production of some longer lived effector memory cells but its absence allows for the generation of long term central memory cells, which are thought to have a higher potential of proliferation on secondary challenge.[17]
DCs and macrophages development
BLIMP-1 has been shown in vitro as a cell lineage determinant in
monocytes, inducing their differentiation into
DCs and
macrophages. It is speculated to have the similar effects in vivo.[6][9] In addition, BLIMP-1 also suppressed myeloid cells from differentiating into
granulocytes, which includes eosinophil, basophil, and neutrophils.[6][9] The role of BLIMP-1 in DCs and macrophages development is a matter of interest because analysis have suggested that DCs, rather than B-cells, is the way in which individual with
single nucleotide polymorphisms (SNP) near BLIMP-1 (specifically, rs548234 in Han Chinese, and rs6568431 in European) are predisposed to
Systemic Lupus Erythematosus (SLE).[6][9]
Osteoclast development
Osteoclasts are multinucleated cells that break down and resorb bone tissues.[6][18] Together with
osteoblasts, which form new bones, osteoclast helps maintain and repair bone in vertebrates.[18] BLIMP-1 directly and indirectly represses anti-osteoclastogenesis genes such as
Bcl6,
IRF8, and
MafB, helping monocytes differentiate into osteoclasts.[6] In mice, insufficient expression of BLIMP-1 in osteoclast progenitors would lead to abnormal development of the skeleton.[6]
Another
GWAS has identified two genetic variations near the PRDM1 gene that predict an increased likelihood of developing a second cancer after radiation treatment for
Hodgkin lymphoma.[19]
Mock BA, Liu L, LePaslier D, Huang S (October 1996). "The B-lymphocyte maturation promoting transcription factor BLIMP1/PRDI-BF1 maps to D6S447 on human chromosome 6q21-q22.1 and the syntenic region of mouse chromosome 10". Genomics. 37 (1): 24–28.
doi:
10.1006/geno.1996.0516.
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Garcia JF, Roncador G, García JF, Sánz AI, Maestre L, Lucas E, et al. (April 2006). "PRDM1/BLIMP-1 expression in multiple B and T-cell lymphoma". Haematologica. 91 (4): 467–474.
PMID16585013.