Profiling germinal center BCR repertoire under enhanced IL-21 signaling

In antibody responses, mutated germinal centre center B (BGC) cells are positively selected for re-cycle entry 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 from B cell receptor (BCR) and follicular helper T (TFH) cells-derived signals, in particular the costimulation through CD40. Here we demonstrate that the TFH cell effector cytokine IL-21 joins BCR and CD40 in supporting BGC selection and reveal that strong IL-21 signallingsignaling prioritises prioritizes ASC differentiation in vivo. BGC cells, compared to non-BGC cells, show significantly reduced IL-21 binding and attenuated signallingsignaling, which is mediated by low cellular heparan sulfate (HS) sulfation. Mechanistically, N-Deacetylase deacetylase and N-Sulfotransferasesulfotransferase-1 (Ndst-1)-mediated N-sulfation of HS in B cells promotes IL-21 binding and signal strength. Ndst-1 is downregulated in BGC cells and upregulated in ASC precursors, suggesting selective desensitisation desensitization to IL-21 in BGC cells. Thus, special biochemical regulation of IL-21 bioavailability and signal strength sets a balance between the stringency and efficiency of GC selection.