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.
Darmoise
Alexandre
A
Immune Disease Institute, Program in Cellular and Molecular Medicine at Children's Hospital, Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
Teneberg
Susann
S
Bouzonville
Lauriane
L
Brady
Roscoe O
RO
Beck
Michael
M
Kaufmann
Stefan H E
SH
Winau
Florian
F
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
D001324:Autoantigens; D008055:Lipids; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors; D000519:alpha-Galactosidase