Lysosomal alpha-galactosidase controls the generation of self lipid antigens for natural killer T cells

Immunity. 2010 Aug 27;33(2):216-28. doi: 10.1016/j.immuni.2010.08.003.


Natural Killer T (NKT) cells are lipid-reactive, CD1d-restricted T lymphocytes important in infection, cancer, and autoimmunity. In addition to foreign antigens, NKT cells react with endogenous self lipids. However, in the face of stimulating self antigen, it remains unclear how overstimulation of NKT cells is avoided. We hypothesized that constantly degraded endogenous antigen only accumulates upon inhibition of alpha-galactosidase A (alpha-Gal-A) in lysosomes. Here, we show that alpha-Gal-A deficiency caused vigorous activation of NKT cells. Moreover, microbes induced inhibition of alpha-Gal-A activity in antigen-presenting cells. This temporary enzyme block depended on Toll-like receptor (TLR) signaling and ultimately triggered lysosomal lipid accumulation. Thus, we present TLR-dependent negative regulation of alpha-Gal-A as a mechanistic link between pathogen recognition and self lipid antigen induction for NKT cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen Presentation
  • Autoantigens / immunology*
  • Cells, Cultured
  • Coculture Techniques
  • Dendritic Cells / immunology
  • Homeostasis
  • Lipids / immunology*
  • Lymphocyte Activation
  • Lysosomes / enzymology
  • Lysosomes / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myeloid Differentiation Factor 88 / deficiency
  • Myeloid Differentiation Factor 88 / immunology
  • Myeloid Differentiation Factor 88 / metabolism
  • Natural Killer T-Cells / enzymology
  • Natural Killer T-Cells / immunology*
  • Signal Transduction
  • Toll-Like Receptors / immunology
  • Toll-Like Receptors / metabolism
  • alpha-Galactosidase / immunology*
  • alpha-Galactosidase / metabolism


  • Autoantigens
  • Lipids
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Toll-Like Receptors
  • alpha-Galactosidase