Identification of domains in IL-16 critical for biological activity

IL-16 is a proinflammatory cytokine implicated in the pathogenesis of asthm a and other conditions characterized by recruitment of CD4(+) T cells to si tes of disease. It is postulated that CD4 is an IL-16 receptor, although ot her receptors or coreceptors may exist. Among several known functions, IL-1 6 is a chemoattractant factor for CD4(+) T cells and it inhibits MLR. We pr eviously reported that an oligopeptide corresponding to the 16 C-terminal r esidues of human IL-16 inhibits chemoattractant activity. To identify funct ional domains with greater precision, shorter oligonucleotides containing n ative or mutated C-terminal IL-16 sequences were tested for IL-16 inhibitio n. Within the 16 C-terminal residues, the minimal peptide RRKS (correspondi ng to Arg(106) to Ser(109)) was shown to mediate inhibition of IL-16 chemoa ttractant activity. Inhibition was lost when either arginine was substitute d with alanine, Point mutations in IL-16 revealed that Arg(107) is critical for chemoattractant activity, but MLR inhibition was unaffected by mutatio n of Arg(107) or even deletion of the C-terminal tail through Arg(106). Del etion of 12 or 22 N-terminal residues of IL-16 had no impact on chemoattrac tant activity, but MLR inhibition was reduced. Deletion of 16 C-terminal pl us 12 N-terminal residues abolished both chemoattractant and MLR-inhibitory activity of IL-16. These data indicate that receptor interactions with IL- 16 that activate T cell migration are not identical with those required for MLR inhibition, and suggest that both N-terminal and C-terminal domains in IL-16 participate in receptor binding or activation.