How Distinct Age-Associated B Cell Subsets Can Protect the Aged from Influenza

ABSTRACT: How Distinct Age-Associated B Cell Subsets Can Protect the Aged from Influenza. With age, the generation of T follicular helpers from naive CD4 T cells, and of germinal center B cells from follicular B cells, both of which are essential for the generation of high affinity antibody (Ab), become highly compromised. Most current vaccines for influenza in the elderly are ineffective at inducing these critical responses. Thus, the elderly, though protected by Ab already in place for pathogens encountered earlier in life, are highly susceptible to new strains of virus (e.g. new yearly variants of influenza) and newly emerged pathogens (e.g. pandemic influenzas, COVID-19). In aged mice, we noted the generation of an unusual population of Ab-secreting B cells in response to live influenza infection. We found they are derived from stimulation of recently described "age-associated B cells" (ABC) rather than conventional naïve follicular B cells. In aged mice influenza-induced ABC (iABC) responses are generated independently of CD4 T cell help, but are strictly depend on stimulation by pathogen- associated "danger" signals. Notably, the ABC are the predominant naïve B cells that respond to influenza infection in aged mice. We find only the IgD ABC subset of naïve ABC, respond, and that IgD ABC include two subsets, T-bet+/CD11c+ and T-bet-/CD11c-. Here we will determine the potential of each of these to respond to infection and generate Ab-secreting cells (AbSC), B cell memory and long-lived Ab-secreting cells in the lung and nasal tissues as well as the spleen, lymph node and bone marrow and define what signals from the influenza infection are needed. We will determine the contribution of the T-bet and non-T-bet responses to protection from reinfection. We will compare the ability of live influenza virus, whole inactivated virus and mRNA-LNP vaccine to generate ABC-derived responses and induce protective immunity, and test if adding infection-associated signals improves this. These results will give us new insights into this novel age-associated immune pathway and should provide new indications of how vaccines can be improved to provide more robust protection to the elderly who currently are highly vulnerable.