Project description:Regulatory T (Treg) cells are required for peripheral tolerance. Recent evidence indicates that Treg cells can adopt specialized differentiation programs in the periphery that are controlled by transcription factors usually associated with T helper differentiation. We demonstrate that expression of the transcription factor Blimp1 defines a population of Treg cells that localize predominantly to mucosal sites and produces IL-10. Blimp1 is required for IL-10 production by these cells and for their tissue homeostasis. A list of differentially expressed genes were identified from this whole-genome expression profiling experiment. Mouse Blimp1 +/gfp and Blimp1 gfp/gfp regulatory T cells were analyzed. Three replicates each.
Project description:Blimp1 is an essential regulator of plasma cells. Here we studied its functions in early plasmablast differentiation by identifying regulated Blimp1 target genes. Blimp1 promoted plasmablast migration and adhesion by controlling many genes involved in these processes. It repressed several transcription factor genes and Aicda, thus silencing B-cell-specific gene expression, antigen presentation and class switch recombination in plasmablasts. It also directly activated genes, leading to increased expression of the plasma cell regulator IRF4 and proteins involved in immunoglobulin secretion. Blimp1 strongly induced immunoglobulin gene transcription by controlling the activity of Igh and Igk 3’ enhancers and regulated the posttranscriptional switch of expression from the membrane-bound to secreted immunoglobulin heavy-chain by activating Ell2. Notably, Blimp1 recruited chromatin-remodeling and histone-modifying complexes to regulate its target gene. Hence, many essential functions of plasma cells are under Blimp1 control.
Project description:To clarify the potential BLIMP1 downstream target regulating PD-L1 expression, we performed proteomics analysis using BLIMP1 Hep3B cells and control cells. Proteomics analysis revealed that SPI1 may serve as a pivotal transcriptional factor that enhances PD-L1 expression by acting as a downstream effector of BLIMP1.
Project description:Follicular regulatory T cells (TFR) are a major cellular source of negative regulation of GC antibody responses. Blimp1 is expressed by the majority of TFR cells within B cell follicles during immune responses, as well as by other tissue-specific subsets of effector Treg (eTreg). However, the potential impact of FoxP3-specific Blimp1 deletion on TFR differentiation and suppressive activity has not been evaluated. To better understand the role of Blimp1 in regulation of TFR differentiation and function, we profiled the differential gene expression in Blimp1-deficient TFR cells compared to WT control TFR cells.
Project description:Regulatory T (Treg) cells are required for peripheral tolerance. Recent evidence indicates that Treg cells can adopt specialized differentiation programs in the periphery that are controlled by transcription factors usually associated with T helper differentiation. We demonstrate that expression of the transcription factor Blimp1 defines a population of Treg cells that localize predominantly to mucosal sites and produces IL-10. Blimp1 is required for IL-10 production by these cells and for their tissue homeostasis. A list of differentially expressed genes were identified from this whole-genome expression profiling experiment.
Project description:As a part of a modelling experiment for transcriptional control of mouse primordial germ cell specification, the transcription factor BLIMP1 was transiently expressed in the mouse p19 embryonal carcinoma cell line and its genome wide binding sites were defined using ChIPseq.
Project description:T follicular helper cells (TFH) are critical for the development and maintenance of germinal centers (GC) and humoral immune responses. During chronic HIV/SIV infection TFH accumulate, possibly as a result of antigen persistence. The HIV/SIV-associated TFH expansion may also reflect lack of regulation by suppressive follicular regulatory CD4+ T-cells (TFR). TFR are natural regulatory T-cells (TREG) that migrate into the follicle and, similarly to TFH, up-regulate CXCR5, Bcl-6, and PD1. Here we identified TFR as CD4+CD25+FoxP3+CXCR5+PD1hiBcl-6+ within lymph nodes of rhesus macaques (RM) and confirmed their localization within the GC by immunohistochemistry. RNA sequencing showed that TFR exhibit a distinct transcriptional profile with shared features of both TFH and TREG, including intermediate expression of FoxP3, Bcl-6, PRDM1, IL-10, and IL-21. In healthy, SIV-uninfected RM, we observed a negative correlation between frequencies of TFR and both TFH and GC B-cells as well as levels of CD4+ T-cell proliferation. Following SIV infection, the TFR/TFH ratio was reduced with no change in the frequency of TREG or TFR within the total CD4+ T-cell pool. Finally, we examined whether higher levels of direct virus infection of TFR were responsible for their relative depletion post-SIV infection. We found that TFH, TFR and TREG sorted from SIV- infected RM harbor comparable levels of cell-associated viral DNA. Our data suggests that TFR may contribute to the regulation and proliferation of TFH and GC B-cells in vivo and that a decreased TFR/TFH ratio in chronic SIV infection may lead to unchecked expansion of both TFH and GC B-cells. TFR, TFH, TREG and bulk CD4 cells were sorted from spleens of 5 uninfected and 5 infected RM.
Project description:Expression profiling of Prdm1 mutant E9.5 placenta was performed using Illumina whole genome V2 arrays. The hypothesis tested in the present study was that Blimp1 regulates the transcription of key genes involved in trophoblast differentiation. We demonstrate that the invading SpA-TGCs display robust Blimp1 expression and Blimp1 functional loss selectively disrupts specification of this discrete TGC sub-type. Transcriptional profiling experiments identified additional SpA-TGC lineage restricted marker genes that potentially regulate placental morphogenesis.
Project description:Transcription factors (TFs) regulate biological events depending on cellular contexts, precise mechanisms for which are elusive. BLIMP1 has been shown to play key roles in many developmental processes, canonically as a transcriptional repressor that targets to proximities of promoters. Here, we systematically and quantitatively characterized genomic binding patterns of BLIMP1 across four distinct, developing cell types; photoreceptor precursors, embryonic intestinal epithelium, plasmablasts, and primordial germ cells (PGCs). BLIMP1-binding sites are highly enriched in genomic regions proximal to transcription start sites (TSSs), majority of which are shared among cell types and are highly occupied by BLIMP1, whereas only a small number of associated genes are regulated consistently among cell types. In contrast, BLIMP1 weakly binds to more distal, cell type-specific sites with divergent recognition sequences, which account for gene regulations much more efficiently in proportion to the magnitude of expression level changes, with notably similar impacts per site among cell types. Various TF motifs contained in the cell type-specific binding sites exhibit only moderate impacts on transcription dynamics and BLIMP1-occupancy levels. On the other hand, germ cells uniquely involve the shared binding sites in the specification, and grossly maintain the binding pattern in late PGCs, accounting for vast majority of the repressive targets. Furthermore, we identified new sequence motifs strongly bound to BLIMP1 especially in the late PGCs, GGGAAA repeats, a few of which are located around key regulators of gametogenesis. These findings provide a foundation for understanding the genomic regulation of BLIMP1 across developmental processes.