Organizing MHC Class II Presentation

Fooksman, David R.

doi:10.3389/fimmu.2014.00158

Cited by 29 publications

(21 citation statements)

References 56 publications

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“…Consistent with these observations, deletion of the cytoplasmic tail increased the lateral mobility of MHCI (43). Clustering of MHCII complexes on the plasma membrane of APCs has also been reported (44)(45)(46). Using SPT approaches, it was shown that MHCII displays hop diffusion on the cell membrane in a manner that it is dependent on the integrity of the actin cytoskeleton (47).…”

Section: Discussionsupporting

confidence: 60%

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

Torreño-Pina

Manzo

Salio

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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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.cell membrane compartmentalization | iNKT cell autoreactivity | protein nanoclustering | single-particle tracking | stimulated emission depletion nanoscopy

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Section: Discussionsupporting

confidence: 60%

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

Torreño-Pina

Manzo

Salio

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Spatial arrangement of TCRs and their pMHC ligands and assembly into organized structures has been suggested to play a decisive role in this 4,5 .…”

Section: Introductionmentioning

confidence: 99%

DNA origami demonstrate the unique stimulatory power of single pMHCs as T-cell antigens

Hellmeier

Platzer

Eklund

et al. 2020

Preprint

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T-cells detect with their T-cell antigen receptors (TCRs) the presence of rare peptide/MHC complexes (pMHCs) on the surface of antigen presenting cells (APCs). How they convert a biochemical interaction into a signaling response is poorly understood, yet indirect evidence pointed to the spatial antigen arrangement on the APC surface as a critical factor. To examine this, we engineered a biomimetic interface based on laterally mobile functionalized DNA origami platforms, which allow for nanoscale control over ligand distances without interfering with the cell-intrinsic dynamics of receptor clustering.We found that the minimum signaling unit required for efficient T-cell activation consisted of two ligated TCRs within a distance of 20 nanometers, if TCRs were stably engaged by monovalent antibody fragments. In contrast, antigenic pMHCs stimulated T-cells robustly as well-isolated entities. These results identify the minimal requirements for effective TCR-triggering and validate the exceptional stimulatory potency of transiently engaging pMHCs.

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“…Creation of chemical contrast by e-beam This is especially true for peptide-MHC class I. Much less is know about MHC class II 18 . lithography, which is subsequently used to recruit the relevant proteins, is an option but is limited due to its high cost.…”

Section: Introductionmentioning

confidence: 99%

Nano-clustering of ligands on surrogate antigen presenting cells modulates T cell membrane adhesion and organization

Dillard

Lellouch

et al. 2016

Integr. Biol.

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We investigate the adhesion and molecular organization of the plasma membrane of T lymphocytes interacting with a surrogate antigen presenting cell comprising glass supported ordered arrays of antibody (α-CD3) nano-dots dispersed in a non-adhesive matrix of polyethylene glycol (PEG). The local membrane adhesion and topography, as well as the distribution of the T cell receptors (TCRs) and the kinase ZAP-70, are influenced by dot-geometry, whereas the cell spreading area is determined by the overall average density of the ligands rather than specific characteristics of the dots. TCR clusters are recruited preferentially to the nano-dots and the TCR cluster size distribution has a weak dot-size dependence. On the patterns, the clusters are larger, more numerous, and more enriched in TCRs, as compared to the homogeneously distributed ligands at comparable concentrations. These observations support the idea that non-ligated TCRs residing in the non-adhered parts of the proximal membrane are able to diffuse and enrich the existing clusters at the ligand dots. However, long distance transport is impaired and cluster centralization in the form of a central supramolecular cluster (cSMAC) is not observed. Time-lapse imaging of early cell-surface contacts indicates that the ZAP-70 microclusters are directly recruited to the site of the antibody dots and this process is concomitant with membrane adhesion. These results together point to a complex interplay of adhesion, molecular organization and activation in response to spatially modulated stimulation.

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Organizing MHC Class II Presentation

Cited by 29 publications

References 56 publications

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

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

DNA origami demonstrate the unique stimulatory power of single pMHCs as T-cell antigens

Nano-clustering of ligands on surrogate antigen presenting cells modulates T cell membrane adhesion and organization

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