PROJECT SUMMARYThe extrafollicular (EF) B cell response generates virus-specific IgM, IgG and IgA in the airway lumenand local lymph nodes as early as 72h after influenza virus infection, correlating temporally with virusclearance. EF responses are distinct in kinetics, function and signaling requirements from the slowergerminal center responses. EF B cell responses habe been largely dismissed as significant in pathogen-induced immunity, as they are though to generate only short-lived plasma cells and low affinity antibodies.Yet, consistent with recent studies on a requirement for high-affinity interaction between BCR andantigen for induction of EF responses, our studies show that a prototypic EF response to HA of influenzaA/Puerto Rico /8/34 generates high-affinity protective antibodies long-term after influenza infection. Thus,identifying this response as a crucial component of primary influenza-infection-induced antiviral immunity.However, immunization with inactivated virus in adjuvant failed to induce EF responses, yet did inducestrong germinal centers, thereby identifying a specific deficit in vaccine-induced humoral immunity, thatmay reduce its efficacy. Because the signals inducing EF responses are unknown, and their protectivecapacity is unclear, they cannot be exploited for therapeutic or prophylactic uses. To overcome thisknowledge gap we propose to test our hypothesis that innate B cell direct signaling drives high affinitylong-term protective antiviral humoral immunity via induction of strong EF responses. Specific Aim #1 willuse gene-targeted mice to identify the receptors and signaling pathways responsible for EF developmentafter influenza infection and complement inactivated influenza vaccines with their corresponding ligandsto generate EF responses. Aim 2 will delineate the molecular targets of these signaling pathways for thedifferentiation of B cells to EF plasma blasts, following the fate of influenza HA-specific B cells. Aim 3 willassess the quality and protective capacity of EF and GC B cell responses. Successful outcome of thesestudies will provide a conceptual advance by demonstrating that EF responses to infection can generatehigh-affinity antibody responses and provide immune protection. Identification of the ligands, signalingpathways and the gene targets that drive EF responses will increase fundamental knowledge on themechanisms of B cell differentiation and open the door for the exploitation of EF responses to enhanceimmunity through therapeutic and prophylactic interventions.
|Effective start/end date||6/9/16 → 5/31/21|
- National Institutes of Health: $485,151.00