Abstract
The interaction of CD4 with MHC class II during helper T-cell activation and effector function is required for the initiation of an adaptive immune response in all gnathostomes. CD4 is comprised of four immunoglobulin domains but most likely arose from an ancestral two-domain homolog. The distal, D1 domain of CD4 binds to non-polymorphic regions of the MHC molecule, but despite the absolute requirement for this interaction, the sequence and structure of this domain are not well conserved through phylogeny. Conversely, the proximal, D4 domain of CD4 contains the binding site of the cytokine IL-16 and is highly conserved in its amino acid structure. IL-16 is a cytokine that has been described in a wide variety of invertebrate and vertebrate species. The CD4-binding residues on IL-16 are highly conserved throughout phylogeny, allowing for promiscuous binding of IL-16 to CD4 between members of unrelated taxa. This chapter aims to present structural, and functional support for the hypothesis that the CD4 co-receptor of the TCR arose from a primordial receptor for IL-16.