A Shocking Use for CD6?

Abstract

CD6, which exists mainly as a transmembrane lymphocyte receptor but has also been detected in a soluble form in serum, is a member of the scavenger receptor cysteine-rich superfamily (SRCR-SF). Noting that some SRCR-SF proteins interact with conserved pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide (LPS) and lipoteichoic acid (LTA), Sarrias et al . incubated a biotin-labeled recombinant protein comprising the extracellular domain of human CD6 (rsCD6) with bacterial suspensions and assessed binding with Western analysis. rsCD6 bound to both Escherichia coli and Staphyloccus aureus in a calcium-dependent manner; binding to E. coli was inhibited by LPS from E. coli , whereas rsCD6 binding to S. aureus was inhibited by LTA from S. aureus . Natural soluble CD6 (nsCD6) purified from human serum was indistinguishable from rsCD6 in terms of its molecular mass (smaller than membrane-associated CD6) and recognition by polyclonal antibodies. Both nsCD6 and rsCD6 bound LPS with an affinity similar to that of CD14 (known for its role in detecting LPS). Less LPS bound to a CD6-deficient line of Jurkat-derived cells (2G5 cells) than bound a daughter line (2G5-CD6.wt) stably transfected with membrane-associated CD6. Phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in response to LPS was enhanced in 2G5-CD6.wt cells compared with 2G5 cells. Furthermore, LPS elicited ERK1/2 phosphorylation in COS-7 cells transfected with CD6 but not a form with a truncated cytoplasmic tail. Intriguingly, administration of rsCD6 to mice before LPS exposure protected against septic shock, an effect associated with decreased concentrations of proinflammatory cytokines in serum. Thus, the authors conclude that CD6 binds PAMPs and that the soluble form may prove useful in the therapy of septic shock. M.-R. Sarrias, M. Farnós, R. Mota, F. Sánchez-Barbero, A. Ibáñez, I. Gimferrer, J. Vera, R. Fenutría, C. Casals, J. Yélamos, F. Lozano, CD6 binds to pathogen-associated molecular patterns and protects from LPS-induced septic shock. Proc. Natl. Acad. Sci. U.S.A. 104 , 11724-11729 (2007). [Abstract] [Full Text]