As the hallmarks of adaptive immunity, B and T cells respond faster and more robustly on subsequent encounters with the same antigen or pathogen. Interleukine-21 (IL-21) is a common gamma chain cytokine that play essential roles in adaptive immunity. Not only does IL-21 support antibody affinity maturation and long-liver plasma cell generation, but it also prevents CD8+ T cell exhaustion. We recently discovered a new mechanism that IL-21 interacts heparan sulfate proteoglycan (HSPG) to control its bioavailbity and signal strength. Such mechanism underlies the IL-21 signalling dynamics in B cells to safeguard optimal humoral immunity. Furthermore, targeting this mechanism by an agonistic antibody to IL-21 can promote cytotoxic function of CD8+ T cells. IL-21 is a promising candidate to boost adaptive immunity.