Tandem peptide epitopes facilitate CD4-dependent activation of T cell clones

• Published in: Immunology and cell biology 1997-04, Vol.75 (2), p.148-153
• Main Authors: Hayball, John D, Fidler, Sarah J, Palliser, Deborah, Rees, Ann DM, Lamb, Jonathan R, Lake, Richard A
• Format: Article
• Language: English
• Subjects: Antigen-Presenting Cells - immunology; CD4-Positive T-Lymphocytes - immunology; dimer of heterodimers; Dimerization; Epitopes - immunology; Epitopes - metabolism; HIV Infections - immunology; HLA-DR1 Antigen - immunology; HLA-DR1 Antigen - metabolism; human immunodeficiency virus; Humans; linked epitopes; Lymphocyte Activation; major histocompatibility complex class II; Oligopeptides - chemistry; Oligopeptides - immunology; Repetitive Sequences, Nucleic Acid
• ISSN: 0818-9641; 1440-1711
• DOI: 10.1038/icb.1997.20

Peptides that consist of two tandemly repeated epitopes joined by a flexible linker have an increased affinity for class II molecules and are more potent at inducing prolireration of T cell clones than monomeric epitopes. The increase in potency of peptides with two epitopes for individual T cell clones is proportional to the relative CD4 dependence of the clones. We show that epitope dimers activate T cell clones that respond sub‐optimally to monomeric epitopes presented by APC from HIV‐infected donors. We hypothesize that HIV+ APC normally fail to stimulate the clones because virally encoded gpl20 sequesters CD4 from the activation complex, but epitope dimers overcome this effect because they are better able to recruit CD4. The αβ heterodimer of human class II (HLA‐DR1) is further ordered as a dimer of heterodimers (superdimer) 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 proliforative response of T cells to antigen by dint of the superdimers having a higher affinity for CD4 than the nominal class II αβ heterodimers.