title: Lysosomal alpha-galactosidase controls the generation of self lipid antigens for natural killer T cells.
abstract: 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.
authors: Immune Disease Institute, Program in Cellular and Molecular Medicine at Children's Hospital, Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
authors: Alexandre
authors: A
authors: Darmoise
authors: Susann
authors: S
authors: Teneberg
authors: Lauriane
authors: L
authors: Bouzonville
authors: Roscoe O
authors: RO
authors: Brady
authors: Michael
authors: M
authors: Beck
authors: Stefan H E
authors: SH
authors: Kaufmann
authors: Florian
authors: F
authors: Winau
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D001324:Autoantigens / Q000276:immunology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology; D006706:Homeostasis; D008055:Lipids / Q000276:immunology*; D008213:Lymphocyte Activation; D008247:Lysosomes / Q000201:enzymology / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000276:immunology / Q000378:metabolism; D055611:Natural Killer T-Cells / Q000201:enzymology / Q000276:immunology*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism; D000519:alpha-Galactosidase / Q000276:immunology* / Q000378:metabolism
chemical_list: D001324:Autoantigens; D008055:Lipids; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors; D000519:alpha-Galactosidase