Aberrant T helper (Th)2 polarization plays a critical role in the pathogenesis of allergic disorders; the etiology remains unclear. Dendritic cells (DCs) express T cell immunoglobulin mucin domain (TIM)4 that ligates TIM1 on CD4 T cells to drive them to become Th2 cells, but the pathogenic source of TIM4 is unknown. Here we report that a significant increase in TIM4 expression in human DCs was observed in response to Staphylococcal enterotoxin B (SEB) stimulation via Toll-like receptor (TLR)2 and nucleotide-binding oligomerization domain (NOD)1 pathway. Coculture SEB-conditioned DCs with naïve CD4 T cells induced Th2 responses that could be abolished using TLR2 or NOD1 or TIM4 or TIM1 with counterpart antibodies or RNA interference. The results demonstrate that Staphylococcus aureus derived SEB promotes the TIM4 production in human DCs. The interaction between TIM4 and TIM1 drives naïve CD4 T cells to develop to Th2 cells.