Interleukin-16 (IL-16) is a chemoattractant cytokine and modulator of T-cell activation.  IL-16 has been identified as a ligand for CD4 which leads to the induction of cell migration in most CD4+ immune cells.  The secreted active form of IL-16 has been detected at sites of Th1-mediated inflammation, such as those seen in autoimmune diseases, ischemic reperfusion injury (IRI) and tissue transplant rejection (1).  Neutralisation of IL-16 recruitment to CD4, using an anti-IL16 antibody, results in significant attenuation of inflammation and disease pathology in IRI (2), as well as in some autoimmune diseases.

Secreted IL-16 is a 121 amino acid protein that contains a characteristic PDZ-domain.  PDZ domains are typically characterised by a well defined globular structure, with a peptide-binding site located in a groove between the αB and βB structural elements, and a highly conserved carboxylate-binding loop (3).  In contrast to other reported PDZ domains, the NMR structure of IL-16 reveals a tryptophan residue obscuring the recognition groove.  The previously reported binding site for CD4 has been located to a C-terminal RRK motif on IL-16, which is distant from the peptide-binding groove (4). We have produced a novel monoclonal antibody against IL-16 and characterized its binding to IL-16 and possible mechanism of inhibition. The structure of the antibody Fab fragment in complex with IL-16 has been solved, revealing that the antibody binding requires a conformational change in the IL-16 involving the rotation of the αB-helix accompanied by movement of the peptide groove obscuring tryptophan residue and consequent opening up the peptide groove for interaction. Our study provides valuable information and new opportunities for the further development of IL-16 targeted therapeutic drugs, including small molecules that mimic the interaction of the antibody.