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IL-21 Shapes the B Cell Response in a Context-Dependent Manner [RNA-seq

ABSTRACT: The cytokine interleukin-21 (IL-21) is a pivotal T cell-derived signal crucial for germinal center (GC) responses, but the precise mechanisms by which IL-21 influences B cell function remain elusive. Here, we investigated the B cell-intrinsic role of IL-21 signaling by employing a novel IL-21 receptor (Il21r) conditional knock-out mouse model and ex vivo culture systems and uncovered a surprising duality of IL-21 signaling in B cells. While IL-21 stimulation of naïve B cells led to Bim-dependent apoptosis, it promoted robust proliferation of pre-activated B cells, particularly class-switched IgG1+ B cells ex vivo. Consistent with this, B cell-specific deletion of Il21r led to a severe defect in IgG1 responses in vivo following immunization. Intriguingly, Il21r-deleted B cells are significantly impaired in their ability to transition from a pre-GC to a GC state following immunization. Although Il21r-deficiency did not affect the proportion of IgG1+ B cells among GC B cells, it greatly diminished the proportion of IgG1+ B cells among the plasmablast/plasma cell population. Collectively, our data suggest that IL-21 serves as a critical regulator of B cell fates, influencing B cell apoptosis and proliferation in a context-dependent manner.

ORGANISM(S): Mus musculus

PROVIDER: GSE280838 | GEO | 2025/01/01

REPOSITORIES: GEO

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Project description:Follicular T helper cells (Tfh) are critical for providing help to B cells for germinal center (GC) formation. Mutations affecting SAP prevent GC formation due to defective T:B cell interactions, yet effects on Tfh cell differentiation remain unclear. We describe the in vitro differentiation of functionally competent “Tfh-like” cells that expressed IL-21, Tfh markers, and Bcl6, and rescued GC formation in SAP-deficient hosts substantially better than other T helper (Th) cells. SAP-deficient Tfh-like cells appeared virtually indistinguishable from wildtype, yet failed to support GCs in vivo. Interestingly, both Tfh-like and in vivo-derived Tfh cells could produce effector cytokines in response to polarizing conditions. Moreover, other Th cell populations could be reprogrammed to obtain Tfh characteristics. ChIP-Seq analyses revealed positive epigenetic markings on Tbx21, Gata3 and Rorc in Tfh-like and ex vivo Tfh cells, and Bcl6 in other Th cells, supporting the concept of plasticity between Tfh and other Th populations. We describe the in vitro differentiation of functionally competent IL-21-producing cells with Tfh-like properties. Importantly, transfer of low numbers of these cells induced GC formation in SAP-deficient hosts more effectively than other in vitro differentiated Th cells, suggesting they represent bona fide Tfh cell precursors. We have chosen the name “Tfh-like” cells for these in vitro differentiated IL-21 producing cells as they exhibit Tfh characteristics, but do not reside within B cell follicles. SAP-deficient Tfh-like cells were virtually indistinguishable from WT, yet nonetheless, failed to effectively contribute to Tfh cells and rescue GC formation in vivo. Evaluation of cytokine production as well as epigenetic chromatin modifications of genes encoding Th cell-specific transcription factors from either in vitro-generated Tfh-like cells or Tfh cells isolated directly ex vivo provided evidence for plasticity between Tfh-like and other Th cell populations. Our results provide insight into the requirements for differentiation and plasticity of Tfh cells, which are critical for the generation of effective long-term humoral immunity. RNA was prepared from subconfluent asynchronously proliferating cells using TRIZOL and purified by RNeasy MinElute Cleanup kit (Qiagen). Hybridization to Affymetrix GeneChip Mouse Genome 430 2.0 arrays was used to generate gene expression profiles of WT Tfh-like and SAP-deficient Tfh-like cells.

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IL-21 Shapes the B Cell Response in a Context-Dependent Manner [RNA-seq

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