Experimental Immunology, Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
Nat Immunol. 2012 Mar 18;13(5):474-80. doi: 10.1038/ni.2245.
The development and maturation of semi-invariant natural killer T cells (iNKT cells) rely on the recognition of self antigens presented by CD1d restriction molecules in thymus. The nature of the stimulatory thymic self lipids remains elusive. We isolated lipids from thymocytes and found that ether-bonded mono-alkyl glycerophosphates and the precursors and degradation products of plasmalogens stimulated iNKT cells. Synthetic analogs showed high potency in activating thymic and peripheral iNKT cells. Mice deficient in the peroxisomal enzyme glyceronephosphate O-acyltransferase (GNPAT), essential for the synthesis of ether lipids, had significant alteration of the thymic maturation of iNKT cells and fewer iNKT cells in both thymus and peripheral organs, which confirmed the role of ether-bonded lipids as iNKT cell antigens. Thus, peroxisome-derived lipids are nonredundant self antigens required for the generation of a full iNKT cell repertoire.
半不变自然杀伤 T 细胞 (iNKT 细胞) 的发育和成熟依赖于其在胸腺中识别由 CD1d 限制分子呈递的自身抗原。刺激性胸腺内自身脂质的性质仍不清楚。我们从胸腺细胞中分离出脂质，发现醚键单烷基甘油磷酸酯以及血小板质的前体和降解产物可刺激 iNKT 细胞。合成类似物在激活胸腺内和外周 iNKT 细胞方面显示出很高的效力。过氧化物酶体酶甘油磷酸 O-酰基转移酶 (GNPAT) 缺失的小鼠，该酶对于醚脂的合成是必需的，其 iNKT 细胞在胸腺内的成熟出现显著改变，并且胸腺和外周器官中的 iNKT 细胞数量减少，这证实了醚键脂质作为 iNKT 细胞抗原的作用。因此，过氧化物体衍生的脂质是生成完整 iNKT 细胞库所必需的非冗余自身抗原。
