Heparan sulfate regulates IL-21 bioavailability and signal strength that control germinal center B cell selection and differentiation

In antibody responses, mutated germinal center B (BGC) cells are positively selected for reentry or differentiation. As the products from GCs, memory B cells and antibody-secreting cells (ASCs) support high-affinity and long-lasting immunity. Positive selection of BGC cells is controlled by signals received through the B cell receptor (BCR) and follicular helper T (TFH) cell–derived signals, in particular costimulation through CD40. Here, we demonstrate that the TFH cell effector cytokine interleukin-21 (IL-21) joins BCR and CD40 in supporting BGC selection and reveal that strong IL-21 signaling prioritizes ASC differentiation in vivo. BGC cells, compared with non-BGC cells, show significantly reduced IL-21 binding and attenuated signaling, which is mediated by low cellular heparan sulfate (HS) sulfation. Mechanistically, N-deacetylase and N-sulfotransferase 1 (Ndst1)–mediated N-sulfation of HS in B cells promotes IL-21 binding and signal strength. Ndst1 is down-regulated in BGC cells and up-regulated in ASC precursors, suggesting selective desensitization to IL-21 in BGC cells. Thus, specialized biochemical regulation of IL-21 bioavailability and signal strength sets a balance between the stringency and efficiency of GC selection. Description Low sulfation of heparan sulfate in BGC cells supports the desensitization to IL-21 and stringent selection for ASC differentiation. An IL-21 reservoir for B cells B cells undergo antigen-driven selection in germinal centers (GCs), enabling some GC B cells to exit and differentiate into antibody-secreting cells (ASC). Positive selection of GC B cells depends on successful integration of signals from the B cell receptor as well as CD40 ligand and IL-21 signals originating from follicular helper T cells. Chen et al. discovered that IL-21 bioavailability is dynamically regulated by heparan sulfate on B cells. Enzymatic N-sulfation of heparan sulfate is suppressed in GC B cells to ensure selection stringency and subsequently upregulated in ASC precursors, establishing a reservoir of bound IL-21 that increases IL-21 signaling and ASC differentiation. These findings provide fresh insights into how IL-21 availability and signal strength influence the fate of GC B cells. —IRW

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