HELPER EFFECTOR FUNCTION OF HUMAN T-CELLS STIMULATED BY ANTI-CD3 MAB CAN BE ENHANCED BY COSTIMULATORY SIGNALS AND IS PARTIALLY DEPENDENT ONCD40-CD40 LIGAND INTERACTION

In this study we have investigated whether anti-CD3-induced human T ce ll help for immunoglobulin production could be enhanced by co-stimulat ion of the T cells via other T cell surface molecules, and the contrib ution of CD40-CD40 ligand interaction to the execution of T helper eff ector function induced by these different stimulatory signals. In a sy stem in which irradiated tonsillar T cells were stimulated with immobi lized anti-CD3 monoclonal antibody (mAb); it was found that ligation o f CD2 with a mitogenic pair of mAb considerably enhanced anti-CD3-indu ced T cell help for immunoglobulin production. Likewise, ligation of C D28 with mAb enhanced T helper activity, although to a lesser extent. Upon addition of anti-CD28 and anti-CD2 mAb together, an even higher i mmunoglobulin 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. Th e 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 F c gamma RII-expressing mouse fibroblasts which were co-transfected wit h human B7. It appeared that B7 could stimulate help for immunoglobuli n production much more efficiently than ligation of CD28 with mAb did. Physical separation of B cells from T cells led to complete abrogatio n of immunoglobulin production. Blocking of CD40 with specific mAb, wh ich have no intrinsic B cell stimulatory properties, or the CD40 ligan d with a soluble CD40-human IgM fusion protein, resulted in dose-depen dent, but only partial, inhibition of T cell-dependent immunoglobulin production with all modes of T cell activation tested. A clear correla tion was found between the induction of CD40 ligand expression on the T cells by the different modes of co-stimulation and subsequent immuno globulin production by the B cells. It is concluded that ligation of C D28 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.