1. Committee on Immunology and
2. Committee on Microbiology, University of Chicago, Chicago, Illinois 60637, USA
3. University of Texas Medical Branch, Department of Pathology, Galveston, Texas 77555, USA
4. Brigham Young University, Department of Chemistry and Biochemistry, Provo, Utah 84602-5700, USA
5. The Scripps Research Institute, Department of Immunology, La Jolla, California 92037, USA
6. These authors contributed equally to this work

Correspondence to: Albert Bendelac^1,6 Correspondence and requests for materials should be addressed to A.B. (Email: abendela@bsd.uchicago.edu) or P.B.S. (Email: paul_savage@byu.edu).

Abstract

CD1d-restricted natural killer T (NKT) cells are innate-like lymphocytes that express a conserved T-cell receptor and contribute to host defence against various microbial pathogens^{1, 2}. However, their target lipid antigens have remained elusive. Here we report evidence for microbial, antigen-specific activation of NKT cells against Gram-negative, lipopolysaccharide (LPS)-negative alpha-Proteobacteria such as Ehrlichia muris and Sphingomonas capsulata. We have identified glycosylceramides from the cell wall of Sphingomonas that serve as direct targets for mouse and human NKT cells, controlling both septic shock reaction and bacterial clearance in infected mice. In contrast, Gram-negative, LPS-positive Salmonella typhimurium activates NKT cells through the recognition of an endogenous lysosomal glycosphingolipid, iGb3, presented by LPS-activated dendritic cells. These findings identify two novel antigenic targets of NKT cells in antimicrobial defence, and show that glycosylceramides are an alternative to LPS for innate recognition of the Gram-negative, LPS-negative bacterial cell wall.

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