Bee venom processes human skin lipids for presentation by CD1a

Bourgeois, Elvire Anne; Subramaniam, Sumithra; Cheng, Tan-Yun; Jong, Annemieke de; Layre, Emilie; Ly, Dalam; Salimi, Maryam; Legaspi, Annaliza; Modlin, Robert L.; Salio, Mariolina; Cerundolo, Vincenzo; Moody, D. Branch; Ogg, Graham S.

doi:10.1084/jem.20141505

Cited by 100 publications

(158 citation statements)

References 62 publications

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“…Thus, it has been previously postulated that the small headless lipids might nest in the CD1a groove and thereby allow direct TCR-CD1a contact, whereas the headgroups would in some way block this TCR-CD1a interaction. While the patterns of antigen sensitivity of BK6, BC2 and Bgp differ, our work resonates with those published studies 10,13,14,22 and plausibly indicates a general mechanism of the autoreactivity of the αβTCR to CD1a.…”

Section: Discussionsupporting

confidence: 91%

“…Nevertheless, the normal human T cell repertoire contains a substantial number of autoreactive CD1a-restricted T cells 13,14,22 , which suggests a physiological role for these T cells in the human immune system. Furthermore, two other CD1a-autoreactive T cell clones (BC2 and Bgp) are activated by CD1a bound to several 'headless' skin-derived hydrophobic lipids 10 , and headgroup-containing lipids, including SM, could inhibit this autoreactive T cell response.…”

Section: Discussionmentioning

confidence: 99%

“…Lysophosphatidylcholine (LPC) was not detected in eluents of CD1a (Fig. 2), but we chose this as a candidate ligand because it is a single-chain version of PC that can be generated through the action of phospholipases 22 is also a known antigen for other CD1 proteins 23,24 . We found that LPC increased the staining of Jurkat.BK6 cells (Fig.…”

Section: Identification Of Permissive and Nonpermissive Ligandsmentioning

confidence: 99%

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αβ T cell antigen receptor recognition of CD1a presenting self lipid ligands

et al. 2015

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A central paradigm in αβ T cell-mediated immunity is the simultaneous co-recognition of antigens and antigen-presenting molecules by the αβ T cell antigen receptor (TCR). CD1a presents a broad repertoire of lipid-based antigens. We found that a prototypical autoreactive TCR bound CD1a when it was presenting a series of permissive endogenous ligands, while other lipid ligands were nonpermissive to TCR binding. The structures of two TCR-CD1a-lipid complexes showed that the TCR docked over the A' roof of CD1a in a manner that precluded direct contact with permissive ligands. Nonpermissive ligands indirectly inhibited TCR binding by disrupting the TCR-CD1a contact zone. The exclusive recognition of CD1a by the TCR represents a previously unknown mechanism whereby αβ T cells indirectly sense self antigens that are bound to an antigen-presenting molecule.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Identification Of Permissive and Nonpermissive Ligandsmentioning

confidence: 99%

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αβ T cell antigen receptor recognition of CD1a presenting self lipid ligands

et al. 2015

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“…These T cells, which can secrete both IL-13 and IFN-γ in allergic patients, can be activated by the generation of novel lipid antigens by naturally occurring enzymes found in various allergen sources, as was recently described for bee venom. 155,156 Given the abundance of lipid antigens in allergens and microbes, a role for CD1a-reactive T cells in asthmatic patients is entirely plausible.…”

Section: Heterogeneity Of T Cells and Influence Of The Tissue Microenmentioning

confidence: 99%

Pathogenic CD4 + T cells in patients with asthma

Muehling

Lawrence

Woodfolk

2017

Journal of Allergy and Clinical Immunology

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Asthma encompasses a variety of clinical phenotypes that involve distinct T cell–driven inflammatory processes. Improved understanding of human T-cell biology and the influence of innate cytokines on T-cell responses at the epithelial barrier has led to new asthma paradigms. This review captures recent knowledge on pathogenic CD4+ T cells in asthmatic patients by drawing on observations in mouse models and human disease. In patients with allergic asthma, TH2 cells promote IgE-mediated sensitization, airway hyperreactivity, and eosinophilia. Here we discuss recent discoveries in the myriad molecular pathways that govern the induction of TH2 differentiation and the critical role of GATA-3 in this process. We elaborate on how cross-talk between epithelial cells, dendritic cells, and innate lymphoid cells translates to T-cell outcomes, with an emphasis on the actions of thymic stromal lymphopoietin, IL-25, and IL-33 at the epithelial barrier. New concepts on how T-cell skewing and epitope specificity are shaped by multiple environmental cues integrated by dendritic cell “hubs” are discussed. We also describe advances in understanding the origins of atypical TH2 cells in asthmatic patients, the role of TH1 cells and other non-TH2 types in asthmatic patients, and the features of T-cell pathogenicity at the single-cell level. Progress in technologies that enable highly multiplexed profiling of markers within a single cell promise to overcome barriers to T-cell discovery in human asthmatic patients that could transform our understanding of disease. These developments, along with novel T cell–based therapies, position us to expand the assortment of molecular targets that could facilitate personalized treatments.

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“…These findings, which were subsequently confirmed by independent research groups [33][34][35], illustrate a mechanism by which lipidspecific lymphocytes can recognize both the head-group and lipid tail to ensure greater specificity of antigen recognition. Recent results obtained with skin resident CD1a restricted T cells demonstrate that the above concept can be extended to lipid recognition in the context of group I CD1 molecules [36 ].…”

Section: The Expanding Repertoire Of Inkt Cell Exogenous Antigensmentioning

confidence: 98%