IL-21R is critical for the development of memory responses

The development of long-term humoral immunity, characterized by the formation of high affinity memory B cells and long-lived plasma cells in the bone marrow, is a major goal of vaccination, but the mechanisms involved in the generation of long-term humoral immunity are not well understood. IL-21 can induce B cell differentiation into plasma cells and influence isotype switching to some subclasses of IgG. Using IL-21R KO mice, we show for the first time a role for the IL-21 pathway in the development of long-term humoral immunity. Antigen specific IgG serum responses to the T cell-dependent antigen, NP-CGG, were delayed in IL-21R KOs, but reached comparable titers to those measured in WT within 3 weeks. The formation of germinal centers, which give rise to long-lived plasma cells and memory B cells, was also delayed in IL-21R KO, but reached similar magnitudes as in WT within 2 weeks. IL-21R KO generated normal numbers of NP-specific IgG plasma cells in their bone marrow at ~1.5 months after immunization. NP-specific serum IgG antibody responses were of similar relative affinity in IL-21R KO and WT at this time, indicating that NP-specific B cells affinity matured in IL-21R KO. However, IL-21R KO failed to generate NP-specific secondary IgG antibody responses following rechallenge with NP-CGG. These results indicate that the IL-21 pathway is necessary for the formation of memory B cell responses but not high affinity long-lived plasma cells.