期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 113, 期 6, 页码 E772-E781出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1514530113
关键词
cell membrane compartmentalization; iNKT cell autoreactivity; protein nanoclustering; single-particle tracking; stimulated emission depletion nanoscopy
资金
- Austrian Science Fund [FWF:13045-B11]
- Spanish Ministry of Economy and Competitiveness [SEV-2015-0522, FIS2014-56107-R]
- Human Frontiers Science Program (HFSP) [GA RGP0027/2012]
- EC FP7-NANO-VISTA Grant [GA 288263]
- LaserLab Europe Grant [GA 284464]
- UK Medical Research Council, UK
- Cancer Research UK Program [C399/A2291]
- Wellcome Trust [084923]
- Medical Research Council [MR/K012118/1]
- ICREA Funding Source: Custom
- MRC [MR/K012118/1, G1000800, MC_UU_12010/1] Funding Source: UKRI
- Cancer Research UK [11331, 17722] Funding Source: researchfish
- Medical Research Council [G1000800, MR/K012118/1, MC_UU_12010/1, G1000800e] Funding Source: researchfish
Invariant natural killer T (iNKT) cells recognize endogenous and exogenous lipid antigens presented in the context of CD1d molecules. The ability of iNKT cells to recognize endogenous antigens represents a distinct immune recognition strategy, which underscores the constitutive memory phenotype of iNKT cells and their activation during inflammatory conditions. However, the mechanisms regulating such tonic activation of iNKT cells remain unclear. Here, we show that the spatiotemporal distribution of CD1d molecules on the surface of antigen-presenting cells (APCs) modulates activation of iNKT cells. By using super-resolution microscopy, we show that CD1d molecules form nanoclusters at the cell surface of APCs, and their size and density are constrained by the actin cytoskeleton. Dual-color single-particle tracking revealed that diffusing CD1d nanoclusters are actively arrested by the actin cytoskeleton, preventing their further coalescence. Formation of larger nanoclusters occurs in the absence of interactions between CD1d cytosolic tail and the actin cytoskeleton and correlates with enhanced iNKT cell activation. Importantly and consistently with iNKT cell activation during inflammatory conditions, exposure of APCs to the Toll-like receptor 7/8 agonist R848 increases nanocluster density and iNKT cell activation. Overall, these results define a previously unidentified mechanism that modulates iNKT cell autoreactivity based on the tight control by the APC cytoskeleton of the sizes and densities of endogenous antigen-loaded CD1d nanoclusters.
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