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Cholera toxin (CT) is a powerful immunomodulator with strong adjuvant activity. Much of this activity is retained by the binding component alone, cholera toxin B subunit (CTB). Little is known about the mechanism of the immunomodulatory activity of CTB. In this study, both CT and CTB were found to dramatically enhance IL-4 production from a T cell clone stimulated with antigen and the B cell hybridoma LB as antigen-presenting cell (APC). Enhancement of cytokine production was seen following pretreatment of the APC with CT or CTB, while pretreatment of the T cells had no effect. Furthermore, stimulatory activity on the APC was stable to fixation with paraformaldehyde, demonstrating that the activity was mediated by a surface molecule on the APC. CT-pretreated APC also enhanced IL-4 production from anti-CD3 mAb-stimulated T cells, indicating that CT was providing a co-stimulatory signal. CT treatment of LB cells did not alter the expression of class II MHC molecules, CTLA-4 counter-receptors, LFA-1 or ICAM-1. When mAb were raised against the CT-pretreated APC, the only antibodies that were found to inhibit IL-4 production were those specific for CTB itself. The antibodies blocked even when the CT or CTB were already bound to the APC, arguing that co-stimulation was provided by a direct interaction with CTB. Blocking experiments suggested that APC-associated CTB molecules are interacting with non-GM1 receptors on the T cells. This novel finding of CTB-mediated T-B interaction provides one of the first potential mechanisms for the adjuvant activity of CTB.