PRDM1

PRDM1/BLIMP-1 is a master transcription factor regulating downstream cytokines. It is activated by TLRs and IRF-4, and is crucial in T cell, B cell, and myeloid lineage cell differentiations.

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]

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 Atf6, 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]

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]

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]

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]

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]

SNPs near the PRDM1 gene have been identified in genome-wide association studies (GWAS) to be linked to lupus (SLE) and rheumatoid arthritis (RA).[9] BLIMP-1 represses the expression of the proinflammatory cytokine Interleukin-6 (IL-6), and cathepsin S (CTSS), which promotes antigen processing and presentation. BLIMP-1 deficiency and IL-6 overexpression were linked to inflammatory bowel disease (IBD) and SLE.[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]

• PRDM1+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• FactorBook PRDM1

This article incorporates text from the United States National Library of Medicine, which is in the public domain.