Leveraging iNKT cells to identify signals driving B cell memory commitment

Abstract Intense scrutiny of the process of memory B cells (MBC) over the last decade has improved our understanding of MBC development especially for vaccines against viruses capable of rapid diversification like SARS-CoV-2. Most memory responses develop in germinal centers (GC), but the constellation of specific signals which commit B cells to a memory fate is poorly understood. Identification of discrete T and B cell factors leading to MBC commitment is hindered by a lack of murine models with essential controls. We report a unique system harnessing iNKT cell help for B cells to create two conditions, both of which expand NP+ B cells in a class-switched primary response, but only one of which produces a MBC response. In the first case, NP+ B cells receive exclusive cognate iNKT cells upon immunization with the Nitrophenyl-haptenated iNKT cell agonist alphaGalactosylCeramide (NP-aGC) leading to an expansion of NP+ GC B cells, but not MBCs. In contrast, NP+ B cells helped by conventional T cells adjuvanted by iNKT cell activation by vaccinating with haptenated protein (NP-KLH) plus aGC drives a conventional GC B cell expansion and development of NP+ MBCs. Interestingly, cognate antigen which does not induce B memory also elicits fewer pre-memory B cells, compared to non-cognate antigen. These different immunization regimens allow a unique comparison of activated B cells recognizing identical epitopes and producing similar primary humoral responses but with contrasting memory outcomes. Importantly, this also controls for the GC environment which is unaccounted for in other model systems. Examination of these B cell populations will better define the transcriptional landscape of MBC and pinpoint key signals which dictate MBC fate. Supported by AAI Careers in Immunology Fellowship 2021