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 demon-strate that the TFH cell effector cytokine interleukin-21 (IL-21) joins BCR and CD40 in supporting BOc 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-sul-fation 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 bio-chemical regulation of IL-21 bioavailability and signal strength sets a balance between the stringency and effi-ciency of GC selection.