CD1-Restricted T Cells at the Crossroad of Innate and Adaptive Immunity

Pereira, Cátia; Macedo, Mário

doi:10.1155/2016/2876275

Cited by 20 publications

(23 citation statements)

References 119 publications

(125 reference statements)

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“…Herein, we did not observe significant modifications in the expression of CD1d molecules by BM-DC incubated with Exo, EV, or VDE fractions (Figure S4 in Supplementary Material) indicating that these L. infantum compounds might use other means to impair CD1d-dependent iNKT cell activation. A similar mechanism leading to the inhibition of iNKT cell activation was also observed with Globotriaosylceramide (Gb3), a glycosphingolipid that accumulates in patients affected by the Fabry disease, a lysosomal storage disorder ( 52 , 53 ).…”

Section: Discussionmentioning

confidence: 59%

Leishmania infantum Exoproducts Inhibit Human Invariant NKT Cell Expansion and Activation

et al. 2017

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Leishmania infantum is one of the major parasite species associated with visceral leishmaniasis, a severe form of the disease that can become lethal if untreated. This obligate intracellular parasite has developed diverse strategies to escape the host immune response, such as exoproducts (Exo) carrying a wide range of molecules, including parasite virulence factors, which are potentially implicated in early stages of infection. Herein, we report that L. infantum Exo and its two fractions composed of extracellular vesicles (EVs) and vesicle-depleted-exoproducts (VDEs) inhibit human peripheral blood invariant natural killer T (iNKT) cell expansion in response to their specific ligand, the glycolipid α-GalactosylCeramide (α-GalCer), as well as their capacity to promptly produce IL-4 and IFNγ. Using plate-bound CD1d and α-GalCer, we found that Exo, EV, and VDE fractions reduced iNKT cell activation in a dose-dependent manner, suggesting that they prevented α-GalCer presentation by CD1d molecules. This direct effect on CD1d was confirmed by the observation that CD1d:α-GalCer complex formation was impaired in the presence of Exo, EV, and VDE fractions. Furthermore, lipid extracts from the three compounds mimicked the inhibition of iNKT cell activation. These lipid components of L. infantum exoproducts, including EV and VDE fractions, might compete for CD1-binding sites, thus blocking iNKT cell activation. Overall, our results provide evidence for a novel strategy through which L. infantum can evade immune responses of mammalian host cells by preventing iNKT lymphocytes from recognizing glycolipids in a TCR-dependent manner.

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Section: Discussionmentioning

confidence: 59%

Leishmania infantum Exoproducts Inhibit Human Invariant NKT Cell Expansion and Activation

et al. 2017

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“…This notion was further supported by the identification of signals of chronic activation in residual iNKT cells from Fabry disease mice [63]. It is known that several GSLs have the capacity to bind to CD1d molecules [14], however, the impact of this binding in NKT cell activation is not clear. One of the explanations proposed in 2006 by Gadola and co-workers was that the high amounts of lipids accumulating in the lysosomes could easily out-compete the endogenous antigens for CD1d binding, thus leading to iNKT cell defects [61].…”

Section: Lysosomal Storage and Nkt Cellsmentioning

confidence: 97%

“…These differences in TCR expression result in distinct antigen specificities (Table 1). While iNKT cells present a preference for α-linked monohexosylceramides, most known antigens for type II NKT cells are β-linked GSLs or phospholipids [11,12,13,14,15,16]. At the moment, there are no cell surface markers that allow for the identification of all type II NKT cells.…”

Section: Nkt Cellsmentioning

confidence: 99%

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From Lysosomal Storage Diseases to NKT Cell Activation and Back

Pereira

Ribeiro

Macedo

2017

IJMS

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Lysosomal storage diseases (LSDs) are inherited metabolic disorders characterized by the accumulation of different types of substrates in the lysosome. With a multisystemic involvement, LSDs often present a very broad clinical spectrum. In many LSDs, alterations of the immune system were described. Special emphasis was given to Natural Killer T (NKT) cells, a population of lipid-specific T cells that is activated by lipid antigens bound to CD1d (cluster of differentiation 1 d) molecules at the surface of antigen-presenting cells. These cells have important functions in cancer, infection, and autoimmunity and were altered in a variety of LSDs’ mouse models. In some cases, the observed decrease was attributed to defects in either lipid antigen availability, trafficking, processing, or loading in CD1d. Here, we review the current knowledge about NKT cells in the context of LSDs, including the alterations detected, the proposed mechanisms to explain these defects, and the relevance of these findings for disease pathology. Furthermore, the effect of enzyme replacement therapy on NKT cells is also discussed.

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“…In primates, CD1d is believed to represent the most deeply conserved member of the CD1 family (Salomonsen 2007.). CD1d receptors can display antigen to specialized iNKT-cells, which are able to mount an earlier response to infection due to their dual role in innate as well as adaptive immunity (Pereira and Macedo 2016). Current evidence indicates that human CD1e does not present antigen (Garcia-Alles et al 2011) but rather assists in antigen loading onto CD1d in lysosomes and endosomes (Cala-De Paepe et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Diversification of CD1 molecules shapes lipid antigen selectivity

Paterson

Al-Zubieri

Barber

2020

Preprint

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Molecular studies of host-pathogen evolution have largely focused on the consequences of variation at protein-protein interaction surfaces. The potential for other microbe-associated macromolecules to promote arms race dynamics with host factors remains unclear. The cluster of differentiation 1 (CD1) family of vertebrate cell surface receptors plays a crucial role in adaptive immunity through binding and presentation of lipid antigens to T-cells. Although CD1 proteins present a variety of endogenous and microbial lipids to various T-cell types, they are less diverse within vertebrate populations than the related major histocompatibility complex (MHC) molecules. We discovered that CD1 genes exhibit a high level of divergence between simian primate species, altering predicted lipid binding properties and T-cell receptor (TCR) interactions. These findings suggest that lipid-protein conflicts have shaped CD1 genetic variation during primate evolution. Consistent with this hypothesis, multiple primate CD1 family proteins exhibit signatures of repeated positive selection at surfaces impacting antigen presentation, binding pocket morphology, and TCR accessibility. Using a molecular modeling approach, we observe that inter-species variation as well as single mutations at rapidly-evolving sites in CD1a drastically alter predicted lipid binding and structural features of the T-cell recognition surface. We further show that alterations in both endogenous and microbial lipid binding affinities influence the ability of CD1a to undergo antigen swapping required for T-cell activation. Together these findings establish lipid-protein interactions as a critical force of host-pathogen conflict and inform potential strategies for lipid-based vaccine development.

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CD1-Restricted T Cells at the Crossroad of Innate and Adaptive Immunity

Cited by 20 publications

References 119 publications

Leishmania infantum Exoproducts Inhibit Human Invariant NKT Cell Expansion and Activation

Leishmania infantum Exoproducts Inhibit Human Invariant NKT Cell Expansion and Activation

From Lysosomal Storage Diseases to NKT Cell Activation and Back

Diversification of CD1 molecules shapes lipid antigen selectivity

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