Abstract

Multivalent nanoparticle vaccines elicit potent T cell-dependent (TD) antibody responses, yet how they initiate CD4 + T cell help remains unclear. Here, we show that antigen-specific B cells function as antigen-presenting cells (APCs) for CD4 + T cell priming across distinct nanoparticle platforms, including AP205 and ferritin. Using SARS-CoV-2 RBD and mpox virus A35 antigens, we demonstrate that B cells and dendritic cells (DCs) act redundantly to initiate early CD4 + T cell activation. In hosts lacking MHC class II expression on non-B cells, B cells alone were sufficient to drive naive CD4 + T cell proliferation. Moreover, B cell-mediated antigen presentation was required for inducing TD responses beyond the draining lymph nodes. These findings reveal a general mechanism by which multivalent nanoparticles engage B cells as APCs and highlight a potential strategy to enhance vaccine-induced immunity.