Systemic 4-1BB stimulation augments extrafollicular memory B cell formation and recall responses during Plasmodium infection 2954

Abstract Description Germinal center (GC)-derived plasma cells (PC) and memory B cells (MBC) are pivotal for the effective clearance of Plasmodium and protection against reinfections. However, suboptimal humoral immune response, emergence of drug-resistant strains and difficulty of developing an efficacious vaccine have drawn keen interest towards host-directed immunotherapeutic approaches. Here, we demonstrate that exogenous stimulation of the costimulatory receptor 4-1BB, using a monoclonal antibody, enhances MBC response and improves protection from rechallenge, even though it delays the effector GC response. Functional and transcriptomic analysis demonstrate that MBCs from mice that received 4-1BB stimulation predominantly had an extrafollicular (EF) origin and showed superior recall and proliferative capacity. In addition, single cell ATAC sequencing revealed that these MBCs possessed a chromatin landscape that is permissive to transcription factors that govern PC differentiation. Importantly, our data also indicate that 3H3-driven protection is dependent on IFNγ and B cell-intrinsic T-BET-IL-9R signaling. In summary, our findings suggest that systemic 4-1BB stimulation in Plasmodium-infected mice promotes the generation of highly functional EF MBCs and signifies the potential of targeting the previously unappreciated IFNγ-T-BET-IL-9R axis to enhance humoral immune memory. Funding Sources Supported by 2024 AAI Careers in Immunology Fellowship; Schweppe Scholar Award (RFUMS); NIH : 1R01AI182217 (to R.V.) Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)