IgD⁺ age-associated B cells are the progenitors of the main T-independent B cell response to infection that generates protective Ab and can be induced by an inactivated vaccine in the aged

Age-associated B cells (ABC) accumulate with age and are associated with autoimmunity and chronic infection. However, their contributions to acute infection in the aged and their developmental pathways are unclear. We find that the response against influenza A virus infection in aged mice is dominated by a Fas⁺GL7⁻ effector B cell population we call infection-induced ABC (iABC). Most iABC express IgM and include antibody-secreting cells in the spleen, lung, and bone marrow. We find that in response to influenza, IgD⁺CD21⁻CD23⁻ABC are the precursors of iABC and become memory B cells. These IgD⁺ABC develop in germ-free mice, so are independent of foreign antigen recognition. The response of ABC to influenza infection, resulting in iABC, is T cell independent and requires both extrinsic TLR7 and TLR9 signals. In response to influenza infection, IgD⁺ABC can induce a faster recovery of weight and higher total anti-influenza IgG and IgM titers that can neutralize virus. Immunization with whole inactivated virus also generates iABC in aged mice. Thus, in unimmunized aged mice, whose other B and T cell responses have waned, IgD⁺ABC are likely the naive B cells with the potential to become Ab-secreting cells and to provide protection from infection in the aged.