B cells can present antigens to CD4⁺ T cells, but it is thought that dendritic cells (DCs) are the primary initiators of naive CD4⁺ T cell responses. Nanoparticles, including virus-like particles (VLPs), are attractive candidates as carriers for vaccines and drug delivery. Using RNA phage Qβ-derived VLP (Qβ-VLP) as a model antigen, we found that antigen-specific B cells were the dominant antigen-presenting cells that initiated naive CD4⁺ T cell activation. B cells were sufficient to induce T follicular helper cell development in the absence of DCs. Qβ-specific B cells promoted CD4⁺ T cell proliferation and differentiation via cognate interactions and through Toll-like receptor signaling-mediated cytokine production. Antigen-specific B cells were also involved in initiating CD4⁺ T cell responses during immunization with inactivated influenza virus. These findings have implications for the rational design of nanoparticles as vaccine candidates, particularly for therapeutic vaccines that aim to break immune tolerance.