Synergism in the activation of human CD8 T cells by cross-linking the T-cell receptor complex with the CD8 differentiation antigen.

Resting human T cells can be activated and induced to proliferate by cross-linking the T-cell receptor complex (Ti/CD3) with anti-CD3 (T3) antibodies, such as OKT3, together with interleukin 2. Here we describe functional properties of another monoclonal anti-CD3 antibody (BMA 030) that, cross-linked in various ways, only weakly stimulates accessory-cell-depleted T-cell cultures. However, when cross-linked to anti-CD4 or anti-CD8 antibodies a markedly enhanced proliferation of the corresponding subpopulation is observed. We have concentrated on the analysis of CD8 cells and have found that BMA 030, when cross-linked together with anti-CD8 (T811), induced proliferation more than 100-fold greater than BMA 030 alone, whereas cross-linking with antibodies to other T-cell membrane antigens (HLA-A, B, or CD5) provided no or marginal synergistic signals. There was no synergistic effect when only one of the two antibodies, BMA 030 or T811, was cross-linked and the other was applied in soluble form. In contrast, each of the two antibodies alone, when applied in soluble form, inhibited activation induced by the cross-linked antibodies. The T-cell differentiation antigen CD8 has been implicated in the major histocompatibility complex (MHC) class I restricted specificity of CD8 T cells. In previous work from other laboratories only the negative influences of soluble anti-CD8 antibodies have been noted. In contrast, our results suggest that cross-linking between Ti/CD3 and CD8 may be a critical event in the activation of mature CD8 cells. We hypothesize that, in antigen-induced T-cell activation, CD8 and Ti/CD3 become cross-linked by their simultaneous binding to class I-associated structures. Such a mechanism, if required for proliferation in early T-cell ontogeny, could generate a selective pressure for CD8 cells to recognize class I-associated antigens.