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IRF4 Haploinsufficiency Impairs Affinity Maturation

ABSTRACT: IRF4 Haploinsufficiency Impairs Affinity Maturation

PROVIDER: PRJNA767888 | ENA |

REPOSITORIES: ENA

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IRF4 Haploinsufficiency Impairs Affinity Maturation

Project description:Single cell RNA seq (scRNA-seq) has emerged as a powerful tool to determine the composition of heterogeneous cell states in a tissue. We found that Irf4+/- antigen specific B cells were functionally impaired in affinity maturation. The goal of this study was to determine whether Irf4+/- antigen specific B cells exhibited distinct cellular composition compared to wild type cells. Sequence data from 8360 cells revealed a similar distribution and numbers of cell states between cells of Irf4+/- or Irf4+/+ genotypes.

2021-10-04 | GSE185188 | GEO

B Cell-Intrinsic IRF4 Haploinsufficiency Impairs Affinity Maturation.

Project description:The germinal center (GC) reaction is a coordinated and dynamic ensemble of cells and processes that mediate the maturation and selection of high-affinity GC B cells (GCBs) from lower-affinity precursors and ultimately results in plasma cell and memory cell fates that exit the GC. It is of great interest to identify intrinsic and extrinsic factors that control the selection process. The transcription factor IRF4, induced upon BCR and CD40 signaling, is essential for the acquisition of plasma cell and GCB cell fates. We hypothesized that beyond this early requirement, IRF4 continuously operates at later phases of the B cell response. We show that IRF4 is expressed in GCBs at levels greater than seen in resting cells and plays a role in efficient selection of high-affinity GCBs. Halving Irf4 gene copy number in an Ag-specific murine B cell model, we found that Ag presentation, isotype switching, GC formation and zonation, somatic hypermutation rates, and proliferation were comparable with cells with a full Irf4 allelic complement. In contrast, Irf4 haploinsufficient GCBs exhibited impaired generation of high-affinity cells. Mechanistically, we demonstrate suboptimal Blimp-1 regulation among high-affinity Irf4 haploinsufficient GCBs. Furthermore, in cotransfer settings, we observed a marked disadvantage of Irf4 haploinsufficient cells for GC entry, evidential of ineffective recruitment of T cell help. We propose that, analogous to its role in early GC entry, IRF4 continues to function in the late phase of the Ab response to promote productive T follicular helper cell interactions and to activate optimal Blimp-1 expression during GC selection and affinity maturation.

| S-EPMC9085970 | biostudies-literature

IRF4 haploinsufficiency in a family with Whipple’s disease

Project description:IRF4 haploinsufficiency in a family with Whipple’s disease

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Haploinsufficiency of BCL6 impairs follicular T-B interactions

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The transcription factor IRF4 is essential for T cell receptor affinity mediated metabolic programming and clonal expansion of T cells [ChIP-seq]

Project description:We demonstrate that transcription factor IRF4 is induced in a T cell receptor (TCR) affinity-dependent manner and functions as a dose-dependent regulator of the metabolic function of activated T cells. IRF4 regulates the expression of key molecules required for aerobic glycolysis of effector T cells, and is essential for clonal expansion and maintenance of effector function of antigen-specific CD8+ T cells. Examination of binding sites of transcription factor IRF4 in mouse CD8+ T cells.

2013-08-17 | E-GEOD-49930 | biostudies-arrayexpress

The transcription factor IRF4 is essential for T cell receptor affinity mediated metabolic programming and clonal expansion of T cells [RNA-seq]

2013-08-17 | E-GEOD-49929 | biostudies-arrayexpress

Regulation of bifurcating B cell trajectories by mutual antagonism between IRF4 and IRF8 (RNA-Seq)

Project description:Upon antigen recognition B cells undertake a bifurcated response in which some cells rapidly differentiate into plasmablasts while others undergo affinity maturation in germinal centers (GC). We uncover a double negative feedback loop between interferon regulatory factors IRF4 and IRF8, which regulates the initial bifurcation of activated B cells as well as the GC response. IRF8 dampens BCR signaling, facilitates antigen specific interaction with helper T cells, and promotes selection of high affinity clones while antagonizing IRF4 driven plasmablast differentiation. Genomic analysis reveals concentration dependent action of IRF4 and IRF8 in regulating distinctive gene expression programs. Stochastic modeling suggests that the double negative feedback is sufficient to initiate bifurcating B cell developmental trajectories.

2015-08-25 | GSE70711 | GEO

Regulation of bifurcating B cell trajectories by mutual antagonism between IRF4 and IRF8 (ChIP-Seq)

2015-08-25 | GSE70710 | GEO

The transcription factor IRF4 is essential for T cell receptor affinity mediated metabolic programming and clonal expansion of T cells [ChIP-seq]

2013-08-17 | GSE49930 | GEO

The transcription factor IRF4 is essential for T cell receptor affinity mediated metabolic programming and clonal expansion of T cells [RNA-seq]

2013-08-17 | GSE49929 | GEO