CD6 binds to pathogen-associated molecular patterns and protects from LPS-induced septic shock

Maria-Rosa Sarrias^*, Montserrat Farnós^*, Rubén Mota, Fernando Sánchez-Barbero, Anna Ibáñez^*, Idoia Gimferrer^*, Jorge Vera^*, Rafael Fenutría^*, Cristina Casals, José Yélamos, and Francisco Lozano^*,¶

*Servei d'Immunologia, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain; Department of Biochemistry and Molecular Biology I, Faculty of Biology, Complutense University of Madrid, 28040 Madrid, Spain; Department of Biochemistry, Molecular Biology, and Immunology, School of Medicine, University of Murcia, 30120 Murcia, Spain; and Department of Immunology, Municipal Institute of Medical Research, Barcelona Biomedical Research Park, 08003 Barcelona, Spain

Received for publication March 26, 2007.

Abstract: CD6 is a lymphocyte receptor that belongs to the scavenger receptor cysteine-rich superfamily. Because some members of the scavenger receptor cysteine-rich superfamily act as pattern recognition receptors for microbial components, we studied whether CD6 shares this function. We produced a recombinant form of the ectodomain of CD6 (rsCD6), which was indistinguishable (in apparent molecular mass, antibody reactivity, and cell binding properties) from a circulating form of CD6 affinity-purified from human serum. rsCD6 bound to and aggregated several Gram-positive and -negative bacterial strains through the recognition of lipoteichoic acid and LPS, respectively. The K_d of the LPS–rsCD6 interaction was 2.69 ± 0.32 x 10^–8 M, which is similar to that reported for the LPS–CD14 interaction. Further experiments showed that membrane CD6 also retains the LPS-binding ability, and it results in activation of the MAPK signaling cascade. In vivo experiments demonstrated that i.p. administration of rsCD6 before lethal LPS challenge significantly improved mice survival, and this was concomitant with reduced serum levels of the proinflammatory cytokines TNF-, IL6, and IL-1. In conclusion, our results illustrate the unprecedented bacterial binding properties of rsCD6 and support its therapeutic potential for the intervention of septic shock syndrome or other inflammatory diseases of infectious origin.

Key Words: bacterial cell component • innate immunity • lymphocyte surface receptor

Conflict of interest statement: This work is the subject of patent application ES200700893 submitted by the University of Barcelona.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0702815104/DC1.

^¶To whom correspondence should be addressed. E-mail: flozano{at}clinic.ub.es

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