HELPER EFFECTOR FUNCTION OF HUMAN T-CELLS STIMULATED BY ANTI-CD3 MAB CAN BE ENHANCED BY COSTIMULATORY SIGNALS AND IS PARTIALLY DEPENDENT ON CD40-CD40 LIGAND INTERACTION

In this study we have investigated whether anti-CD3-induced human T cell help for immunoglobulin production could be enhanced by co-stimulation of the T cells via other T cell surface molecules, and the contribution of CD40-CD40 ligand interaction to the execution of T helper effector function induced by these different stimulatory signals. In a system in which irradiated tonsillar T cells were stimulated with immobilized anti-CD3 monoclonal antibody (mAb); it was found that ligation of CD2 with a mitogenic pair of mAb considerably enhanced anti-CD3-induced T cell help for immunoglobulin production. Likewise, ligation of CD28 with mAb enhanced T helper activity, although to a lesser extent. Upon addition of anti-CD28 and anti-CD2 mAb together, an even higher immunoglobulin production was observed. This combination resulted in a four- to fivefold increase in immunoglobulin production as compared to cultures in which T cells were stimulated with anti-CD3 mAb alone. The effect of ligation with B7, the natural ligand of CD28, was studied in a system which utilizes the presentation of anti-CD3 mAb on human Fc gamma RII-expressing mouse fibroblasts which were co-transfected with human B7. It appeared that B7 could stimulate help for immunoglobulin production much more efficiently than ligation of CD28 with mAb did. Physical separation of B cells from T cells led to complete abrogation of immunoglobulin production. Blocking of CD40 with specific mAb, which have no intrinsic B cell stimulatory properties, or the CD40 ligand with a soluble CD40-human IgM fusion protein, resulted in dose-dependent, but only partial, inhibition of T cell-dependent immunoglobulin production with all modes of T cell activation tested. A clear correlation was found between the induction of CD40 ligand expression on the T cells by the different modes of co-stimulation and subsequent immunoglobulin production by the B cells. It is concluded that ligation of CD28 and/or CTLA-4, and of CD2 can generate co-stimulatory signals for T cell help for immunoglobulin production, which was found to be only partially dependent on the CD40-CD40 ligand interaction.