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

• 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Andra medicinska och farmaceutiska grundvetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Other Basic Medicine (hsv//eng)

Nyckelord

Animals

Antigen Presentation

Autoantigens

immunology

Cells

Cultured

Coculture Techniques

Dendritic Cells

immunology

Homeostasis

Lipids

immunology

Lymphocyte Activation

Lysosomes

enzymology

immunology

Mice

Mice

Inbred C57BL

Mice

Knockout

Myeloid Differentiation Factor 88

deficiency

immunology

metabolism

Natural Killer T-Cells

enzymology

immunology

Signal Transduction

Toll-Like Receptors

immunology

metabolism

alpha-Galactosidase

immunology

metabolism

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)