To investigate the role of human platelets in initiating Ag-specific contact sensitivity (CS), a mouse model employing human platelets was used. Intravenous injection of immune lymphoid cells containing Ag-specific CS-effector Thy1+ B220- T cells that were depleted of CS-initiating Thy1+, B220+ cells together with human platelets presensitized in vitro with Ag-specific IgE mAb led to elicitation of CS responses in recipient mice. The fact that this response was blocked by preincubation of platelets with an irrelevant IgE or with a mixture of anti-Fc epsilonRI alpha mAb and anti-Fc epsilonRII mAb suggested that IgE Fc epsilonR on platelets were involved. When platelets that were presensitized with Ag-specific IgE mAb were incubated in vitro with specific Ag in the presence of fresh mouse serum, a significant net release of [3H]serotonin (5-hydroxytryptamine, 5-HT) was observed. Furthermore, in vitro depletion of 5-HT from platelets or in vivo pretreatment of recipients with a 5-HT2A receptor antagonist (ketanserin) abolished the IgE-dependent CS initiation mediated by platelets. These results show that human platelets can initiate T cell-dependent CS responses through IgE mAb, and this CS initiation is mediated by 5-HT released from the platelets in an Ag-specific manner.