Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections

Nature, 434: 525-529 (2005)

Speaker:陳銘祥                           Time: 13:10-14:00
Commentator:黎煥耀 老師                  Place: 601

 CD1 is a family of MHC-like molecules expressed on the antigen presenting cells (APCs) that can capture lipid antigen to stimulate various T lymphocytes. One group of this family, CD1d, can be recognized by a semi-invariant mouse Vα14-Jα18/Vβ8 or human Vα24-Jα18/Vβ11 TCR on natural killer T (NKT) cells. CD1d-restricted NKT cells have been shown to fight against various microbial infections by rapid release of cytokines, such as IFN-γ, in the early stage of infection. In the presence of the  LPS-positive bacteria, such as Salmonella typhimurim, the APCs could activate mouse NKT cells by producing IL-12 via the Toll-like receptor (TLR) signaling pathway to promote bacterial clearance without presenting LPS¹. However, whether NKT cells can directly recognize foreign microbial antigen remains unclear. In this study, the authors found that coculture of the mouse NKT cells with heat-killed S. typhimurim, and LPS–negative Sphingomonas capsulata or Ehrlichia muris in the presence of dendritic cells (DCs) could result in the release of IFN-γ. However, only S. typhimurim,  but not S. capsulata or E. muris, coculture system required TLR signaling by DCs. The Hexb^-/- DCs which lacked the endogenous lysosomal glycosphingolipid ligand, isoglobotrihexosylceramide (iGb3)², also failed to stimulate mouse NKT cells when coculture with S. typhimurim, but not S. capsulata or E. muris. The cell walls of S. capsulata or E. muris contain the glycosphingolipids which are similar to α-galactosylceramide (α-GalCer) that when loaded onto CD1d could strongly stimulate both human and mouse NKT cells. The authors further demonstrated that the synthetic S. capsulate cell wall glycosphingolipid could activate mouse and human ^{NKT cells}, and the CD1d-tetramer loaded with these compounds could stain both NKT cells. These results suggest the activation of NKT cells by direct interaction with the microbial glycolipids. Moreover, although NKT-deficient mice delayed the bacterial clearance during S. capsulate infection, at high infection dose, the mortality of NKT-deficient mice was significantly reduced. This was probably because the NKT cells which were activated in the presence of large amount of bacteria explosively released IFN-γand IL-12 and resulted in septic shock in the early stage. These findings suggest different monitoring mechanisms and dual physiological roles of NKT cells during various microbial infection.

References:

1. Brigl, M., Bry, L., Kent, S. C., et al. Mechanism of CD1d-restricted natural killer T cell activation during microbial infection. Nature Immunol. 4, 1230–1237 (2003).

2. Zhou, D. et al. Lysosomal glycosphingolipid recognition by NKT cells. Science 306, 1786–1789 (2004).

3. Jochen, M. et al. Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections. Nature. 434, 525-529 (2005).