CD4-Ia interactions can occur in the absence of T-cell receptor/antigen-Ia recognition

The T-cell differentiation antigen, CD4, is expressed by major histocompatibility (MHC) class II restricted T lymphocytes. CD4+CD8- T cells use their T-cell receptor to recognize foreign antigens in association with MHC class II products (Ia). The association between CD4 expression and restriction by MHC class II products has led to the hypothesis that CD4 may interact with monomorphic determinants of MHC class II molecules. A large body of experimental evidence suggests that CD4 interaction with MHC class II molecules leads to an increase in the binding avidity of T cell-stimulator cell interactions. A direct test for a functional CD4-MHC class II interaction in T-cell activation requires a separate evaluation of CD4-Ia interactions from T-cell receptor (TcR)-antigen (Ag)/Ia recognition. However, a separate evaluation proves difficult since the T-cell receptor and CD4 may interact with the same MHC class II molecule. In this report, we use a T-cell activation protocol where TcR-Ag/Ia recognition is replaced by TcR complex-anti-CD3 antibody interactions. Therefore, the affinity of the TcR complex for its ligand (the anti-CD3 mAb) is independent from MHC expression on target cells and allows a separate evaluation of the role of accessory molecules in T-cell activation. We have analysed the effects of monoclonal anti-MHC class II antibodies on the activation of a CD4+ T-cell hybridoma in the absence of its TcR restricting MHC class II molecule (I-Ek) but in the presence of unrelated MHC class II molecules (I-Ed, I-Ad). The data obtained indicate a functional interaction between the CD4 molecule and a non-polymorphic region of the MHC class II product in T-cell triggering.