We previously demonstrated that CD81^–/– mice fail to develop T_h2‐biased immune responses and allergen‐induced airway hyper‐reactivity. Because CD81 is expressed on both activated T and on B cells, we examined the role of CD81 expression by each cell type. We established an in vitro system by backcrossing the CD81 deletion to TCR transgenic (Tg) mice and to BCR Tg mice. Here we demonstrate that CD81 expression by T cells is critical for their induction of IL‐4 synthesis by B cells. CD81^–/– TCR Tg T cells were impaired in IL‐4 production compared to CD81^+/+ TCR Tg T cells, whereas CD81^–/– and CD81^+/+ BCR Tg B cells induced equivalent amounts of IL‐4 in CD81^+/+ TCR Tg T cells. CD81^–/– TCR Tg T cells expressed reduced levels of ICOS, GATA‐3, STAT6 and phosphorylated STAT6 when activated by antigen‐presenting B cells. Taken together, these results indicate that CD81 expression by T cells greatly enhances cognate T–B cell interactions and greatly augments intracellular activation pathways leading to T_h2 polarization.