Glycosphingolipids Activated NKT Cells

Abstract

A subset of natural killer T (NKT) cells with a specialized form of the T cell receptor (TCR) containing an invariant TCR α chain (in mice Vα14i, in humans Vα24i) that recognizes antigens presented by the major histocompatibility complex (MHC)-like molecule CD1d is involved in the immune response to microbial pathogens. Presentation of lipids or lipopeptides by the CD1 class of MHC-like molecules displayed on dendritic cells is now a recognized mechanism for the activation of T cells. However, the microbial and possibly endogenous lipids that activate these CD1d-restricted NKT cells have remained elusive. Kinjo et al . and Mattner et al . report the identification of microbial glycosphingolipid ligands that activate NKT cells. Both groups reported that Gram-negative bacteria that do not possess lipopolysaccharide (LPS), which is a Toll-like receptor (TLR) agonist, activated CD1d-restricted NKT cells both in vivo and in vitro. Both groups also identified specific glycosphingolipids from the Gram-negative bacteria that activated the NKT cells. CD1d-restricted NKT cells are unusual in that they are abundant even in the absence of prior stimulation and do not require clonal expansion. Thus, their response is most similar to an innate immune response in kinetics and in magnitude. Mattner et al . reported that the response to Gram-positive bacteria, such as Salmonella , required TLR signaling and presentation of an endogenous glycosphingolipid, isoglobotrihexosylceramide (iGb3), by dendritic cells. Thus, CD1d-restricted NKT cells appear to have two mechanisms for activation in response to microbial pathogens: an indirect mechanism that involves TLR recognition of LPS by dendritic cells, leading to the presentation of an endogenous lipid for Gram-positive bacteria, and a direct mechanism whereby the NKT cells are directly activated by microbial glycosphingolipids presented by CD1d molecules. Y. Kinjo, D. Wu, G. Kim, G.-W. Xing, M. A. Poles, D. D. Ho, M. Tsuji, K. Kawahara, C.-H. Wong, M. Kronenberg, Recognition of bacterial glycosphingolipids by natural killer T cells. Nature 434 , 520-525 (2005). [PubMed] J. Mattner, K. L. DeBord, N. Ismail, R. D. Goff, C. Cantu, III, D. Zhou, P. Saint-Mezard, V. Wang, Y. Gao, N. Yin, K. Hoebe, O. Schneewind, D. Walker, B. Beutler, L. Teyton, P. B. Savage, A. Bendelac, Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections. Nature 434 , 525-529 (2005). [PubMed]