TANDEM PEPTIDE EPITOPES FACILITATE CD4-DEPENDENT ACTIVATION OF T-CELLCLONES

Peptides that consist of two tandemly repeated epitopes joined by a fl exible linker have an increased affinity for class II molecules and ar e more potent at inducing proliferation of T cell clones than monomeri c epitopes. The increase in potency of peptides with two epitopes for individual T cell clones is proportional to the relative CD4 dependenc e of the clones. We show that epitope dimers activate T cell clones th at respond sub-optimally to monomeric epitopes presented by APC From H IV-infected donors. We hypothesize that HIV+ APC normally fail to stim ulate the clones because vitally encoded gp120 sequesters CD4 from the activation complex, but epitope dimers overcome this effect because t hey are better able to recruit CD4. The alpha beta heterodimer of huma n class II (HLA-DR1) is further ordered as a dimer of heterodimers (su perdimer) at least in its crystal form. Since class II molecules have an open-ended antigen binding groove, the superdimer is theoretically permissive of stable binding of two peptide epitopes linked in tandem. Our data support a role for the MHC class II dimer of heterodimers in amplifying the proliferative response of T cells to antigen by dint o f the superdimers having a higher affinity for CD4 than the nominal cl ass II alpha beta heterodimers.