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The actin cytoskeleton modulates the activation of iNKT cells by segregating CD1d nanoclusters on antigen-presenting cells

Torreno-Pina, Juan A. ; Manzo, Carlo ; Salio, Mariolina ; Aichinger, Michael C. ; Oddone, Anna ; Lakadamyali, Melike ; Shepherd, Dawn ; Besra, Gurdyal S. ; Cerundolo, Vincenzo ; Garcia-Parajo, Maria F.

Proceedings of the National Academy of Sciences - PNAS, 2016-02, Vol.113 (6), p.E772-E781 [Periódico revisado por pares]

United States: National Academy of Sciences

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Título:
The actin cytoskeleton modulates the activation of iNKT cells by segregating CD1d nanoclusters on antigen-presenting cells
Autor: Torreno-Pina, Juan A. ; Manzo, Carlo ; Salio, Mariolina ; Aichinger, Michael C. ; Oddone, Anna ; Lakadamyali, Melike ; Shepherd, Dawn ; Besra, Gurdyal S. ; Cerundolo, Vincenzo ; Garcia-Parajo, Maria F.
Assuntos: Actin Cytoskeleton - metabolism ; Antigen-Presenting Cells - metabolism ; Antigens ; Antigens, CD1d - metabolism ; Biological Sciences ; Cell Line ; Cell Membrane - metabolism ; Cells ; Cytoskeleton ; Diffusion ; Galactosylceramides - metabolism ; Genotype & phenotype ; Humans ; Inflammation - pathology ; Lymphocyte Activation ; Models, Biological ; Molecules ; Monocytes - metabolism ; Nanoparticles - chemistry ; Natural Killer T-Cells - metabolism ; PNAS Plus ; Protein Transport ; Proteins ; Spatio-Temporal Analysis
É parte de: Proceedings of the National Academy of Sciences - PNAS, 2016-02, Vol.113 (6), p.E772-E781
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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2V.C. and M.F.G-P. contributed equally to this work.
Edited by Jennifer Lippincott-Schwartz, National Institutes of Health, Bethesda, MD, and approved December 22, 2015 (received for review July 23, 2015)
Author contributions: J.A.T.-P., V.C., and M.F.G.-P. designed research; J.A.T.-P., M.S., M.C.A., and A.O. performed research; J.A.T.-P., C.M., M.S., M.L., D.S., and G.S.B. contributed new reagents/analytic tools; J.A.T.-P., C.M., and M.F.G.-P. analyzed data; and V.C. and M.F.G.-P. wrote the paper.
1Present address: EveliQure Biotechnologies GmbH, A-1030 Vienna, Austria.
Descrição: 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 superresolution 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.
Editor: United States: National Academy of Sciences
Idioma: Inglês

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The actin cytoskeleton modulates the activation of iNKT cells by segregating CD1d nanoclusters on antigen-presenting cells

Torreno-Pina, Juan A. ; Manzo, Carlo ; Salio, Mariolina ; Aichinger, Michael C. ; Oddone, Anna ; Lakadamyali, Melike ; Shepherd, Dawn ; Besra, Gurdyal S. ; Cerundolo, Vincenzo ; Garcia-Parajo, Maria F.

United States: National Academy of Sciences

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