B cells targeting parasites capture spatially linked antigens to secure T cell help.

T cell-dependent antibody responses have been well studied in the context of small proteins and viruses. However, how B cells acquire and process antigens from large pathogens such as parasites remains poorly understood. Here, using Plasmodium sporozoites (SPZs) as a model, we investigated the formation of protective antibody responses against the circumsporozoite protein (CSP), a vaccine antigen expressed on the surfaces of SPZs. CSP-specific B cells took up CSP and bystander surface antigens during SPZ immunization and could obtain both intramolecular and intermolecular T cell help. Furthermore, prior exposure to blood-stage parasites-which predominantly share internal but not surface antigens with SPZs-can hinder the generation of anti-CSP antibodies. Thus, spatial relationships between the target antigens can affect CD4 T cell help to B cells. These data show how B cells obtain antigen for presentation to T cells and why malaria-exposed individuals have impaired antibody responses to CSP.