Atypical sideways recognition of CD1a by autoreactive γδ T cell receptors

Wegrecki, Marcin; Ocampo, Tonatiuh A.; Gunasinghe, Sachith D.; Borstel, Anouk von; Tin, Shin Yi; Reijneveld, Josephine F.; Cao, Thinh Phat; Gully, Benjamin S.; Nours, Jérôme Le; Moody, D. Branch; Rhijn, Ildiko Van; Rossjohn, Jamie

doi:10.1038/s41467-022-31443-9

Cited by 20 publications

(19 citation statements)

References 58 publications

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“…The panel of tested CD1a variants consisted of single point mutations and multiple mutants, as illustrated in Fig. S3A , and a chimeric variant where the α1 and α2 domains of CD1a were fused to the α3 domain of human CD1d 30 . Biotinylated wild-type (WT) and mutant proteins were bound to streptavidin beads and stained with anti-CD1a antibodies to assess epitope binding.…”

Section: Resultsmentioning

confidence: 99%

CD1a promotes systemic manifestations of skin inflammation

et al. 2022

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Inflammatory skin conditions are increasingly recognised as being associated with systemic inflammation. The mechanisms connecting the cutaneous and systemic disease are not well understood. CD1a is a virtually monomorphic major histocompatibility complex (MHC) class I-like molecule, highly expressed by skin and mucosal Langerhans cells, and presents lipid antigens to T-cells. Here we show an important role for CD1a in linking cutaneous and systemic inflammation in two experimental disease models. In human CD1a transgenic mice, the toll-like receptor (TLR)7 agonist imiquimod induces more pronounced splenomegaly, expansion of the peripheral blood and spleen T cell compartments, and enhanced neutrophil and eosinophil responses compared to the wild-type, accompanied by elevated skin and plasma cytokine levels, including IL-23, IL-1α, IL-1β, MCP-1 and IL-17A. Similar systemic escalation is shown in MC903-induced skin inflammation. The exacerbated inflammation could be counter-acted by CD1a-blocking antibodies, developed and screened in our laboratories. The beneficial effect is epitope dependent, and we further characterise the five best-performing antibodies for their capacity to modulate CD1a-expressing cells and ameliorate CD1a-dependent systemic inflammatory responses. In summary, we show that a therapeutically targetable CD1a-dependent pathway may play a role in the systemic spread of cutaneous inflammation.

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Section: Resultsmentioning

confidence: 99%

CD1a promotes systemic manifestations of skin inflammation

et al. 2022

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“…For example, CD1a proteins display foreign lipoproteins such as the mycobacterial didehydroxy-mycobactin (Zajonc et al, 2005) or they can present cellular lipids such as sulfatide (Zajonc et al, 2003). Unlike what is observed in γδ TCRs (Wegrecki et al, 2022), binding of sulfatide to CD1a abolishes the αβ T-cell response due to a local conformational change in the protein (Cotton et al, 2021). The lipid-binding groove of CD1a is characterized by the presence of a double hydrophobic compartment cavity termed the A′ and F′ pockets with the A′ role being to present the lipid antigen to TCRs (Zajonc et al, 2005).…”

Section: Frontiers In Molecular Biosciencesmentioning

confidence: 99%

“…As identified in other sulfatide-binding sites, a tyrosine residue (Y84) faces the sulfatide head group, whereas H38 makes contacts with one of the acyl chains of the sphingolipid ( Figure 3B ). Whereas CD1a serves as a sulfatide-independent ligand for TCRs, the CD1-γδ TCR can also complex sulfatide with a K D ranging between 10–22 μM ( Table 1 ) ( Wegrecki et al, 2022 ). The crystal structure of CD1-γδ TCR-sulfatide reveals that a CD1a-bound sulfatide head group emerges from the F′ portal and is about 13Å from the TCR γ subunit, which it might explain why sulfatide does not inhibit γδ TCR binding to CD1a ( Wegrecki et al, 2022 ).…”

Section: Distinct Sulfatide-binding Principlesmentioning

confidence: 99%

“…Whereas CD1a serves as a sulfatide-independent ligand for TCRs, the CD1-γδ TCR can also complex sulfatide with a K D ranging between 10–22 μM ( Table 1 ) ( Wegrecki et al, 2022 ). The crystal structure of CD1-γδ TCR-sulfatide reveals that a CD1a-bound sulfatide head group emerges from the F′ portal and is about 13Å from the TCR γ subunit, which it might explain why sulfatide does not inhibit γδ TCR binding to CD1a ( Wegrecki et al, 2022 ). The sulfatide-binding site in TLR-bound CD1a is consistent with that reported earlier for the CD1a-sulfatide complex ( Figure 3B ) ( Zajonc et al, 2003 ).…”

Section: Distinct Sulfatide-binding Principlesmentioning

confidence: 99%

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The repertoire of protein-sulfatide interactions reveal distinct modes of sulfatide recognition

Capelluto

2022

Front. Mol. Biosci.

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Sulfatide is an abundant glycosphingolipid in the mammalian nervous system, kidney, trachea, gastrointestinal tract, spleen, and pancreas and is found in low levels in other tissues. Sulfatide is characterized by the presence of a sulfate group in the hydrophilic galactose moiety, with isoforms differing in their sphingosine base and the length, unsaturation, and hydroxylation of their acyl chain. Sulfatide has been associated with a variety of cellular processes including immune responses, cell survival, myelin organization, platelet aggregation, and host-pathogen interactions. Structural studies of protein-sulfatide interactions markedly advanced our understanding of their molecular contacts, key-interacting residues, orientation of the sulfatide in its binding site, and in some cases, sulfatide-mediated protein oligomerization. To date, all protein-sulfatide interactions are reported to display dissociation constants in the low micromolar range. At least three distinct modes of protein-sulfatide binding were identified: 1) protein binding to short consensus stretches of amino acids that adopt α-helical-loop-α-helical conformations; 2) sulfatide-bound proteins that present the sulfatide head group to another protein; and 3) proteins that cage sulfatides. The scope of this review is to present an up-to-date overview of these molecular mechanisms of sulfatide recognition to better understand the role of this glycosphingolipid in physiological and pathological states.

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“…Surface proteins of pathogens or cells, recognized through protein-protein interactions or more broadly receptor-ligand interactions (RLIs), are important markers for disease diagnosis and treatment [1][2][3][4][5][6][7] . Notably, the dynamic distribution of protein receptors is usually nonuniform and discontinuous, with the low expression of some proteins, which make it difficult to accurately identify and isolate targets [8][9][10][11] .…”

Section: Introductionmentioning

confidence: 99%

Modular DNA-origami-based nanoarrays enhanced cell binding-affinity through “lock-key” interaction

Mao

Lin

Chen

et al. 2022

Preprint

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Surface proteins of cells are generally recognized through receptor-ligand interactions (RLIs) in disease diagnosis, but their nonuniform spatial distribution and high-order structure lead to low binding-affinity. Constructing nano-topologies that match the spatial distribution of membrane proteins to improve binding-affinity remains a challenge. Inspired by the multi-antigen recognition of immune synapses, we developed modular DNA-origami-based nanoarrays with multivalent aptamers. By adjusting the valence and inter-spacing of the aptamers, we construct specific nano-topology to match the spatial distribution of target protein clusters and avoid potential steric hindrance. We found that the nanoarrays significantly enhanced the binding-affinity of target cells, and synergistically recognize low-affinity antigen-specific cells. In addition, using DNA nanoarrays for the detection of clinical circulation tumor cells successfully verified its precise recognition ability and high affinity RLIs. Such nanoarrays will further promote the potential application of DNA materials in clinical detection and even cell membrane engineering.

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Atypical sideways recognition of CD1a by autoreactive γδ T cell receptors

Cited by 20 publications

References 58 publications

CD1a promotes systemic manifestations of skin inflammation

CD1a promotes systemic manifestations of skin inflammation

The repertoire of protein-sulfatide interactions reveal distinct modes of sulfatide recognition

Modular DNA-origami-based nanoarrays enhanced cell binding-affinity through “lock-key” interaction

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