溶酶体α-半乳糖苷酶控制自然杀伤 T 细胞自身脂质抗原的产生。
Lysosomal alpha-galactosidase controls the generation of self lipid antigens for natural killer T cells.
机构信息
Immune Disease Institute, Program in Cellular and Molecular Medicine at Children's Hospital, Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
出版信息
Immunity. 2010 Aug 27;33(2):216-28. doi: 10.1016/j.immuni.2010.08.003.
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.
摘要
自然杀伤 T（NKT）细胞是脂类反应性、CD1d 限制性 T 淋巴细胞，在感染、癌症和自身免疫中具有重要作用。除了外源抗原外，NKT 细胞还与内源性自身脂质发生反应。然而，在面对刺激自身抗原时，目前尚不清楚如何避免 NKT 细胞的过度刺激。我们假设，只有在溶酶体中抑制α-半乳糖苷酶 A（alpha-Gal-A）时，不断降解的内源性抗原才会积累。在这里，我们发现 alpha-Gal-A 缺乏会导致 NKT 细胞的强烈激活。此外，微生物诱导抗原呈递细胞中 alpha-Gal-A 活性的抑制。这种暂时的酶阻断依赖于 Toll 样受体（TLR）信号，并最终触发溶酶体脂质积累。因此，我们提出 TLR 依赖性的 alpha-Gal-A 抑制作为病原体识别和 NKT 细胞自身脂质抗原诱导之间的机制联系。
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