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

Abstract

AbstractOur understanding of T-cell-dependent humoral responses has been largely shaped by studies involving model antigens such as recombinant proteins and viruses1,2. In these contexts, B cells internalize the entire antigen or pathogen, and present a range of antigens to helper CD4+T cells to initiate the humoral response. However, this model does not account for large pathogens (such as parasites) that are too large to be taken up by individual B cells, and the mechanisms by which B cells acquire and present antigens from large complex pathogens to T cells remain poorly understood. Here we usedPlasmodium, the causative parasite of malaria, as a model to investigate the requirements for T cell help for B cells targeting thePlasmodiumsurface circumsporozoite protein (CSP). UponPlasmodiumsporozoite (SPZ) immunization, CSP-specific B cells can form a synapse-like structure with SPZs and take up CSP and non-CSP surface antigens. As a result, CSP-specific B cells can receive help from CD4+T cells specific to antigens that are located on the surface but not cytosol of thePlasmodiumSPZ. Therefore, B cells can obtain help, not only from T cells with the same protein specificity, but also from T cells specific for spatially linked antigens. This flexibility in T cell help may enhance the initiation and maintenance of humoral immune responses to complex pathogens.