4-1BBL signaling aids B cell activation but limits proliferation during experimental malaria

Several costimulatory and coinhibitory signaling axis have been reported to modulate anti-Plasmodium immune response, albeit the precise role of 4-1BB:4-1BBL axis has yet to be investigated. Here, we show that while complete loss of 4-1BB resulted in heightened parasite burden, impaired germinal center (GC) responses and memory B cell (MBC) recall. The absence of 4-1BBL however, minimally affected parasite load or GC responses, while disrupting humoral immune memory. Strikingly, therapeutic blockade of 4-1BBL early during infection derailed both humoral effector and memory response phenocopying 4-1BB-/- data, an effect that was absent when 4-1BBL was blocked at effector timepoints. Importantly, 4-1BBL blockade any timepoint during the course of infection invariably compromised MBC recall even when the GC response remained intact. Our results indicate that 4-1BBL signaling is required for optimal B cell activation but, its absence, paradoxically leads to expansion of a highly proliferative cell population while shrinking the MBC population. Our study highlights the pivotal role of 4-1BBL signaling in governing B cell responses during Plasmodium infection.