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CD4 can physically associate with the CD3-T-cell receptor complex as visualized in cocapping experiments. This association occurs when the T-cell receptor is cross-linked by certain anti-variable region antibodies that appear to induce a conformational change in the receptor such that it associate with CD4. Similar association has been observed in earlier studies with the same cloned helper T cell when the physiological ligand, antigen-class II major histocompatibility complex molecule, is bound by the T-cell receptor. The ability of anti-T-cell receptor antibodies to induce the T-cell receptor-CD4 association correlates with a 100-fold increase in the ability of the antibody to activate the T cell. This suggests that the complex of CD4 and the T-cell receptor act synergistically in T-cell activation, thus readily explaining the commonly observed association of CD4 expression with class II major histocompatibility complex-restricted antigen recognition. This association could also play a role in infection by human immunodeficiency virus.

Physical association of CD4 and the T-cell receptor can be induced by anti-T-cell receptor antibodies.