Extent of MHC Clustering Regulates Selectivity and Effectiveness of T Cell Responses

Anikeeva, Nadia; Fischer, Nicholas O.; Blanchette, Craig D.; Sykulev, Yuri

doi:10.4049/jimmunol.1801196

Cited by 9 publications

(3 citation statements)

References 47 publications

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“…Since the expression of a particular protein and subsequent production of its antigenic peptides can vary at different times (e.g., over the course of a viral infection), we speculate that Tspan5 association with complexes upon release from the PLC could help cocluster more pMHC complexes with the same peptide and thereby further enhance the clustering/stimulation of cognate TCRs. MHC I clusters may also facilitate rebinding of CD8 to cognate and noncognate complexes ( 62 , 63 ) and clustering of CD8-associated Lck has been reported to enhance stimulation ( 64 , 65 ). Presumably, Tspan5–MHC I clusters enhance T cell stimulation through their effects on TCR and CD8 clustering, but could also possibly affect other parameters, such as TCR mechanosensing ( 66 – 68 ).…”

Section: Discussionmentioning

confidence: 99%

Tetraspanin-5–mediated MHC class I clustering is required for optimal CD8 T cell activation

Colbert

Cruz

Baer

et al. 2022

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

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MHC molecules are not randomly distributed on the plasma membrane but instead are present in discrete nanoclusters. The mechanisms that control formation of MHC I nanoclusters and the importance of such structures are incompletely understood. Here, we report a molecular association between tetraspanin-5 (Tspan5) and MHC I molecules that started in the endoplasmic reticulum and was maintained on the plasma membrane. This association was observed both in mouse dendritic cells and in human cancer cell lines. Loss of Tspan5 reduced the size of MHC I clusters without affecting MHC I peptide loading, delivery of complexes to the plasma membrane, or overall surface MHC I levels. Functionally, CD8 T cell responses to antigen presented by Tspan5-deficient dendritic cells were impaired but were restored by antibody-induced reclustering of MHC I molecules. In contrast, Tspan5 did not associate with two other plasma membrane proteins, Flotillin1 and CD55, with or the endoplasmic reticulum proteins Tapasin and TAP. Thus, our findings identify a mechanism underlying the clustering of MHC I molecules that is important for optimal T cell responses.

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Section: Discussionmentioning

confidence: 99%

Tetraspanin-5–mediated MHC class I clustering is required for optimal CD8 T cell activation

Colbert

Cruz

Baer

et al. 2022

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

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“… 91 However, this result is not comparable to that reported by Douglas et al, 88 Hellmeier et al 90 assembled up to two TCR ligands on DNA origami that performed two-dimensional motion, while Vale et al 85 assembled 1–72 TCR ligands and the DNA origami was immobilized on a glass surface. Considering that pMHC forms clusters on the surface of natural antigen-presenting cells, 92 an influence of the spatial organization of pMHC on TCR activation cannot be ruled out.…”

Section: Regulating Immunoreceptor Signaling With Functional Dnamentioning

confidence: 99%

Functional DNA as a Molecular Tool in Regulating Immunoreceptor–Ligand Interactions

Sun

Shen

et al. 2023

JACS Au

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During immune responses, activating ligands would trigger dynamic spatiotemporal organization of immunoreceptors at the cell interface, governing the fate and effector functions of immune cells. To understand the biophysical mechanisms of immunoreceptor signaling, diverse tools, including DNA technologies, have been developed to manipulate receptor–ligand interactions during the immune activation process. With great capability in the controllable assembly of biomolecules, functional DNA-based precise arrangement of immune molecules at cell interfaces has provided a powerful means in revealing the principles of immunoreceptor triggering, even at the single-molecule level. In addition, precisely regulating immunoreceptor–ligand interactions with functional DNA has been applied in immunotherapies of major diseases. This Perspective will focus on the recent advances in exploring immunoreceptor signaling with functional DNA as the molecular tool as well as the applications of functional DNA mediated regulation of immunoreceptor activation. We also outline the challenges and opportunities of applying functional DNA in immune modulation and immunotherapy.

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“…Eph receptors, such as EphA2 (130) and EphB2 (131), have been activated in this way, suggesting that Eph receptors rely on clustering for activity. TCR also responds more efficiently to dense clusters of peptide-major histocompatibility complex (pMHC) ligands than sparse ones (132). Various applications and findings of ligand nanopatterning studies are reviewed in Ref.…”

Section: Receptor Clusteringmentioning

confidence: 99%

Membrane receptor activation mechanisms and transmembrane peptide tools to elucidate them

Westerfield

Barrera

2020

Journal of Biological Chemistry

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Single-pass membrane receptors contain extracellular domains that respond to external stimuli and transmit information to intracellular domains through a single transmembrane (TM) α-helix. Because membrane receptors have various roles in homeostasis, signaling malfunctions of these receptors can cause disease. Despite their importance, there is still much to be understood mechanistically about how single-pass receptors are activated. In general, single-pass receptors respond to extracellular stimuli via alterations in their oligomeric state. The details of this process are still the focus of intense study, and several lines of evidence indicate that the TM domain (TMD) of the receptor plays a central role. We discuss three major mechanistic hypotheses for receptor activation: ligand-induced dimerization, ligand-induced rotation, and receptor clustering. Recent observations suggest that receptors can use a combination of these activation mechanisms and that technical limitations can bias interpretation. Short peptides derived from receptor TMDs, which can be identified by screening or rationally developed on the basis of the structure or sequence of their targets, have provided critical insights into receptor function. Here, we explore recent evidence that, depending on the target receptor, TMD peptides cannot only inhibit but also activate target receptors and can accommodate novel, bifunctional designs. Furthermore, we call for more sharing of negative results to inform the TMD peptide field, which is rapidly transforming into a suite of unique tools with the potential for future therapeutics.

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Extent of MHC Clustering Regulates Selectivity and Effectiveness of T Cell Responses

Abstract: This information is current as Responses Selectivity and Effectiveness of T Cell Extent of MHC Clustering Regulates

Cited by 9 publications

References 47 publications

Tetraspanin-5–mediated MHC class I clustering is required for optimal CD8 T cell activation

Tetraspanin-5–mediated MHC class I clustering is required for optimal CD8 T cell activation

Functional DNA as a Molecular Tool in Regulating Immunoreceptor–Ligand Interactions

Membrane receptor activation mechanisms and transmembrane peptide tools to elucidate them

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