Keller Christian W, Loi Monica, Ewert Svenja, Quast Isaak, Theiler Romina, Gannagé Monique, Münz Christian, De Libero Gennaro, Freigang Stefan, Lünemann Jan D
a Institute of Experimental Immunology, Laboratory of Neuroinflammation, University of Zurich , Zurich , Switzerland.
b Institute of Experimental Immunology, Laboratory of Viral Immunobiology, University of Zurich , Zurich , Switzerland.
Autophagy. 2017 Jun 3;13(6):1025-1036. doi: 10.1080/15548627.2017.1297907. Epub 2017 Mar 15.
Invariant natural killer T (iNKT) cells are innate T cells with powerful immune regulatory functions that recognize glycolipid antigens presented by the CD1D protein. While iNKT cell-activating glycolipids are currently being explored for their efficacy to improve immunotherapy against infectious diseases and cancer, little is known about the mechanisms that control CD1D antigen presentation and iNKT cell activation in vivo. CD1D molecules survey endocytic pathways to bind lipid antigens in MHC class II-containing compartments (MIICs) before recycling to the plasma membrane. Autophagosomes intersect with MIICs and autophagy-related proteins are known to support antigen loading for increased CD4 T cell immunity. Here, we report that mice with dendritic cell (DC)-specific deletion of the essential autophagy gene Atg5 showed better CD1D1-restricted glycolipid presentation in vivo. These effects led to enhanced iNKT cell cytokine production upon antigen recognition and lower bacterial loads during Sphingomonas paucimobilis infection. Enhanced iNKT cell activation was independent of receptor-mediated glycolipid uptake or costimulatory signals. Instead, loss of Atg5 in DCs impaired clathrin-dependent internalization of CD1D1 molecules via the adaptor protein complex 2 (AP2) and, thus, increased surface expression of stimulatory CD1D1-glycolipid complexes. These findings indicate that the autophagic machinery assists in the recruitment of AP2 to CD1D1 molecules resulting in attenuated iNKT cell activation, in contrast to the supporting role of macroautophagy in CD4 T cell stimulation.
不变自然杀伤T（iNKT）细胞是具有强大免疫调节功能的先天性T细胞，可识别由CD1D蛋白呈递的糖脂抗原。虽然目前正在探索激活iNKT细胞的糖脂在改善针对传染病和癌症的免疫治疗方面的功效，但对于体内控制CD1D抗原呈递和iNKT细胞激活的机制知之甚少。CD1D分子在循环至质膜之前，会监测内吞途径，以在含有MHC II类的区室（MIIC）中结合脂质抗原。自噬体与MIIC相交，并且已知自噬相关蛋白可支持抗原加载以增强CD4 T细胞免疫。在此，我们报告，在树突状细胞（DC）中特异性缺失必需自噬基因Atg5的小鼠在体内表现出更好的CD1D1限制性糖脂呈递。这些效应导致抗原识别后iNKT细胞细胞因子产生增强，以及在少动鞘氨醇单胞菌感染期间细菌载量降低。增强的iNKT细胞激活独立于受体介导的糖脂摄取或共刺激信号。相反，DC中Atg5的缺失通过衔接蛋白复合物2（AP2）损害了CD1D1分子的网格蛋白依赖性内化，从而增加了刺激性CD1D1 - 糖脂复合物的表面表达。这些发现表明，自噬机制有助于将AP2募集到CD1D1分子上，从而导致iNKT细胞激活减弱，这与巨自噬在CD4 T细胞刺激中的支持作用相反。
