The actin cytoskeleton modulates the activation of invariant NKT cells by segregating CD1d nanoclusters on antigen presenting cells
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 i...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Journal article |
| Published: |
National Academy of Sciences
2016
|
| _version_ | 1797097403511209984 |
|---|---|
| author | Cerundolo, V Salio, M Shepherd, D Torreno-Pina, J Manzo, C Aichinger, M Oddone, A Bestra, G Garcia-Parajo, M |
| author_facet | Cerundolo, V Salio, M Shepherd, D Torreno-Pina, J Manzo, C Aichinger, M Oddone, A Bestra, G Garcia-Parajo, M |
| author_sort | Cerundolo, V |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T04:55:00Z |
| format | Journal article |
| id | oxford-uuid:d6488eb1-1923-49e2-8757-94e9251f6f21 |
| institution | University of Oxford |
| last_indexed | 2024-03-07T04:55:00Z |
| publishDate | 2016 |
| publisher | National Academy of Sciences |
| record_format | dspace |
| spelling | oxford-uuid:d6488eb1-1923-49e2-8757-94e9251f6f212022-03-27T08:32:24ZThe actin cytoskeleton modulates the activation of invariant NKT cells by segregating CD1d nanoclusters on antigen presenting cellsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:d6488eb1-1923-49e2-8757-94e9251f6f21Symplectic Elements at OxfordNational Academy of Sciences2016Cerundolo, VSalio, MShepherd, DTorreno-Pina, JManzo, CAichinger, MOddone, ABestra, GGarcia-Parajo, MInvariant 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. |
| spellingShingle | Cerundolo, V Salio, M Shepherd, D Torreno-Pina, J Manzo, C Aichinger, M Oddone, A Bestra, G Garcia-Parajo, M The actin cytoskeleton modulates the activation of invariant NKT cells by segregating CD1d nanoclusters on antigen presenting cells |
| title | The actin cytoskeleton modulates the activation of invariant NKT cells by segregating CD1d nanoclusters on antigen presenting cells |
| title_full | The actin cytoskeleton modulates the activation of invariant NKT cells by segregating CD1d nanoclusters on antigen presenting cells |
| title_fullStr | The actin cytoskeleton modulates the activation of invariant NKT cells by segregating CD1d nanoclusters on antigen presenting cells |
| title_full_unstemmed | The actin cytoskeleton modulates the activation of invariant NKT cells by segregating CD1d nanoclusters on antigen presenting cells |
| title_short | The actin cytoskeleton modulates the activation of invariant NKT cells by segregating CD1d nanoclusters on antigen presenting cells |
| title_sort | actin cytoskeleton modulates the activation of invariant nkt cells by segregating cd1d nanoclusters on antigen presenting cells |
| work_keys_str_mv | AT cerundolov theactincytoskeletonmodulatestheactivationofinvariantnktcellsbysegregatingcd1dnanoclustersonantigenpresentingcells AT saliom theactincytoskeletonmodulatestheactivationofinvariantnktcellsbysegregatingcd1dnanoclustersonantigenpresentingcells AT shepherdd theactincytoskeletonmodulatestheactivationofinvariantnktcellsbysegregatingcd1dnanoclustersonantigenpresentingcells AT torrenopinaj theactincytoskeletonmodulatestheactivationofinvariantnktcellsbysegregatingcd1dnanoclustersonantigenpresentingcells AT manzoc theactincytoskeletonmodulatestheactivationofinvariantnktcellsbysegregatingcd1dnanoclustersonantigenpresentingcells AT aichingerm theactincytoskeletonmodulatestheactivationofinvariantnktcellsbysegregatingcd1dnanoclustersonantigenpresentingcells AT oddonea theactincytoskeletonmodulatestheactivationofinvariantnktcellsbysegregatingcd1dnanoclustersonantigenpresentingcells AT bestrag theactincytoskeletonmodulatestheactivationofinvariantnktcellsbysegregatingcd1dnanoclustersonantigenpresentingcells AT garciaparajom theactincytoskeletonmodulatestheactivationofinvariantnktcellsbysegregatingcd1dnanoclustersonantigenpresentingcells AT cerundolov actincytoskeletonmodulatestheactivationofinvariantnktcellsbysegregatingcd1dnanoclustersonantigenpresentingcells AT saliom actincytoskeletonmodulatestheactivationofinvariantnktcellsbysegregatingcd1dnanoclustersonantigenpresentingcells AT shepherdd actincytoskeletonmodulatestheactivationofinvariantnktcellsbysegregatingcd1dnanoclustersonantigenpresentingcells AT torrenopinaj actincytoskeletonmodulatestheactivationofinvariantnktcellsbysegregatingcd1dnanoclustersonantigenpresentingcells AT manzoc actincytoskeletonmodulatestheactivationofinvariantnktcellsbysegregatingcd1dnanoclustersonantigenpresentingcells AT aichingerm actincytoskeletonmodulatestheactivationofinvariantnktcellsbysegregatingcd1dnanoclustersonantigenpresentingcells AT oddonea actincytoskeletonmodulatestheactivationofinvariantnktcellsbysegregatingcd1dnanoclustersonantigenpresentingcells AT bestrag actincytoskeletonmodulatestheactivationofinvariantnktcellsbysegregatingcd1dnanoclustersonantigenpresentingcells AT garciaparajom actincytoskeletonmodulatestheactivationofinvariantnktcellsbysegregatingcd1dnanoclustersonantigenpresentingcells |