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Siglec-G on B cells restrains the germinal center response by controlling T cell help during positive selection

ABSTRACT: The germinal center (GC) reaction requires tight regulation of B cell and T follicular helper (Tfh) cell interactions to ensure B cell expansion and antibody affinity maturation, while preventing oncogenesis. However, regulatory mechanisms fine-tuning B-T cell interactions within the GC to prevent aberrant activation and proliferation remain incompletely understood. Here, we identify Siglec-G, the mouse ortholog of human Siglec-10, as an immune checkpoint that restrains the GC by dampening B-T cell interactions. Selective and temporal ablation of Siglec-G on B cells after immunization triggers GC hyperplasia and enhanced plasma cell and antibody output. While Siglec-G is dispensable in B cell receptor-mediated processes, it acts as an intrinsic inhibitory receptor of B-T cell interactions in the GC, ultimately limiting Myc and mTORC activation within positively selected GC B cells. Trans interactions of Siglec-G and its glycan ligands on Tfh likely contribute in fine-tuning the strength of bidirectional signaling following contact between GC B cells and Tfh cells. This interaction is further reinforced by glycan remodeling that occurs in the GC, resulting in concurrent decreased in glycan ligands on GC B cells and increased in glycan ligands on Tfh. Moreover, APEX2-based proximity labeling revealed several candidate Siglec-G/10 binding partners on T cells, including BTLA, CD6, and Slamf6, which are known negative regulators of Tfh cell activation. Taken together, our findings identified that Siglec-G acts as a GC checkpoint receptor, restricting B cell proliferation by tuning T cell help following B-T cell interactions.

ORGANISM(S): Mus musculus

PROVIDER: GSE333139 | GEO | 2026/05/27

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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Siglec-G on B cells restrains the germinal center response by controlling T cell help during positive selection

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