Lysosomal α-Galactosidase Controls the Generation of Self Lipid Antigens for Natural Killer T Cells

被引：99

作者：

Darmoise, Alexandre ^{[1
,5
]}

Teneberg, Susann ^{[2
]}

Bouzonville, Lauriane ^{[1
]}

Brady, Roscoe O. ^{[3
]}

Beck, Michael ^{[4
]}

Kaufmann, Stefan H. E. ^{[5
]}

Winau, Florian ^{[1
,5
]}

机构：

[1] Harvard Univ, Sch Med, Dept Pathol,Immune Dis Inst, Childrens Hosp,Program Cellular & Mol Med, Boston, MA 02115 USA

[2] Univ Gothenburg, Dept Med Biochem & Cell Biol, Inst Biomed, S-40530 Gothenburg, Sweden

[3] NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA

[4] Johannes Gutenberg Univ Mainz, Childrens Hosp, D-55131 Mainz, Germany

[5] Max Planck Inst Infect Biol, Dept Immunol, D-10117 Berlin, Germany

来源：

IMMUNITY | 2010年 / 33卷 / 02期

关键词：

INVARIANT NKT CELLS; ENZYME REPLACEMENT; IMMUNE-RESPONSE; CD1D TETRAMERS; ACTIVATION; RECOGNITION; MICE; MATURATION; RECEPTORS; MOLECULES;

D O I：

10.1016/j.immuni.2010.08.003

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Natural Killer T (NKT) cells are lipid-reactive, CD1 drestricted 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.

引用

页码：216 / 228

页数：13

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