CCL28, a chemokine that is found in saliva and breast milk, has a dual role in mucosal protection according to a recent functional study published in The Journal of Immunology. Not only does this chemokine attract antibody-secreting cells, but it also has the unexpected capacity to kill microorganisms directly.

Several previous reports have indicated that chemokines and antimicrobial peptides — key weapons in the arsenal of the innate immune system — might be functionally related. Similar to chemokines, certain mammalian antibacterial peptides can attract leukocytes by acting on seven-transmembrane receptors. And, some chemokines have been reported to have antimicrobial activity at high doses in vitro. But, a physiological role for these activities has not been reported.

CCL28, which was discovered only recently, is expressed most abundantly at mucosal sites, and it is known to signal through the receptors CCR10 and CCR3. Kunio Hieshima and co-workers found that the epithelial cells of the salivary glands are the main source of CCL28, and they identified a population of CCR10- and CCR3-expressing cells in single-cell suspensions of mouse salivary glands. These cells, which have the morphology and cell-surface phenotype of plasma cells, respond vigorously to CCL28 in migration assays. So, one function of CCL28 is probably the recruitment of plasma cells to the salivary glands.

CCL28 was found to be present in human saliva and milk at high concentrations. The authors had also noticed that the carboxy-terminal segment of CCL28 has a high histidine content, and closer examination showed that it is similar in sequence to the antimicrobial peptide histatin-5. Together, this evidence provided the initial clue that CCL28 might have a second, more direct role in mucosal defences.

The authors tested the antimicrobial activity of CCL28 and found that it could kill various microbial pathogens — including the fungus Candida albicans and the bacteria Streptococcus mutans, Klebsiella pneumoniae and Staphylococcus aureus — apparently by disrupting the plasma membrane.

Although the concentrations of CCL28 in milk and saliva are lower than the doses that have been found to be effective in killing assays, the authors point out that the chemokine is probably concentrated on epithelial-cell surfaces by binding heparan sulphate. Of note, the closest relative of CCL28, CCL27, does not share its antimicrobial activity.

So, did chemokines emerge initially as antimicrobial peptides before evolving their chemotactic functions, or is the microbicidal activity of CCL28 a later adaptation, arising by convergent evolution? The evolutionary origin of the dual functionality of CCL28 remains an intriguing unresolved issue.