Mechanisms and Consequences of Antigen Presentation by CD1

The identification of immunoactive agents for clinical and mechanistic applications is a very active area of research. In this vein, analogues of the potent immunostimulant KRN 7000 with diverse cytokine profiles have attracted considerable attention. Herein, we report on the synthesis and activity for four new C-glycosides of KRN 7000, 11-phenylundecanoyl and 11-p-fluorophenylundecanoyl derivatives of C-KRN 7000, 2,3-bis-epi-C-KRN 7000 and the reverse amide of C-KRN 7000. In mice, compared to C-KRN 7000, 2,3-bis-epi-C-KRN 7000 stimulated higher release of the anti-inflammatory cytokine IL-4 and lower release of the inflammatory cytokines IFN-γ and IL-12. The phenyl terminated alkanoyl and reverse amide analogues were inactive. These data suggest that structure activity effects for KRN 7000 are not necessarily additive and their use in the design of new analogues will require an improved understanding of how subtle structural changes impact on cytokine activity.

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“…18,19,20 This assemblage stimulates the production of cytokines. Against this backdrop, we were interested in the new C -glycosides 7 – 10 .…”

Section: Introductionmentioning

confidence: 99%

Synthesis and biological activities of C-glycosides of KRN 7000 with novel ceramide residues

Altiti

Zhang

et al. 2017

Carbohydrate Research

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“…The activation of iNKT cells by glycolipids can enhance resistance in several infectious diseases models, and these cells seem to be constantly activated in vivo by endogenous self‐ligands . Our ex vivo analyses of whole blood cells, patients with ACL demonstrated an increase in CD69 expression in iNKT cells compared to all study groups, which was independent of TLA stimulation.…”

Section: Discussionmentioning

confidence: 61%

“…A synthetic glycolipid α‐GalCer was shown to enhance resistance against Trypanosoma cruzi and Toxoplama gondi infections . The iNKT cells are known to recognize endogenous antigens including α‐ and β‐GalCers and glucosylceramides (GlcCers), isoglobotrihexosylceramide (iGb3), ganglioside D3 (GD3), ether‐bonded lipids and glycerophospholipids such as phosphatidylinositol (PI), phosphatidylethanolamine (PE) and lyso‐PC …”

Section: Introductionmentioning

confidence: 99%

Dual immune effect of iNKT cells considering human cutaneous and visceral leishmaniasis: An example of cell plasticity according to different disease scenarios

et al. 2018

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Although the semi-invariant natural killer T cells (iNKT) are a small subpopulation of cells in the peripheral blood, they are presumed to play a role in early stages of infection against various pathogens, including protozoa. This work investigates the activation status and cytokine profile of iNKT cells during human Leishmania infantum and Leishmania braziliensis infection. We studied iNKT cells in patients with symptomatic active visceral leishmaniasis (AVL) (n = 8), patients with symptomatic active cutaneous leishmaniasis (ACL) (n = 13), negative endemic controls (NEC) (n = 6) and non-endemic controls (NonEC) (n = 6), with and without total Leishmania antigen stimulus (TLA). The number of iNKT cells in the peripheral blood of patients with ACL and AVL unaltered in relation to control groups. Moreover, the iNKT cells from ACL showed a hyperactivation profile compared to patients with AVL. Additionally, TLA induced IFN-gamma production in iNKT cells from patients with ACL, while in iNKT of patients with AVL, TLA induced a decrease in this cytokine. Higher IL-17 and IL-10 production by iNKT cells from patients with ACL were also observed compared to all other groups. There were no changes in iNKT IL-10-producing cells in AVL after TLA stimulation. However, TLA induced increase in IL-10 in iNKT cells in patients with ACL. These findings suggest that, although iNKT cells showed distinct profiles in patients with ACL and AVL, they play a dual role in immune modulation in both Leishmania infections.

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“…Moreover, the use of sc MHC technology can be extended to investigation of non-classical MHC molecules such as HLA-E. Sc HLA-E has been described before, and its expression has been shown to inhibit human T cell activation 45 . Another non-classical MHC molecule of interest is CD1, which presents lipids instead of peptides 46 . Sc constructs consisting of CD1 heavy chain and β2-microglobulin have been shown to be expressed on the cell surface and to bind relevant lipid ligands 47 .…”

Section: Discussionmentioning

confidence: 99%

Use of Single Chain MHC Technology to Investigate Co-agonism in Human CD8+ T Cell Activation

Xiang

Hamidinia

Choo

et al. 2019

JoVE

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Non-stimulatory self peptide MHC (pMHC) complexes do not induce T cell activation and effector functions, but can enhance T cell responses to agonist pMHC, through a process termed co-agonism. This protocol describes an experimental system to investigate co-agonism during human CD8+ T cell activation by expressing human MHC class I molecules presenting predetermined peptides as single polypeptides (single chain MHC) in a xenogeneic cell line. We expressed single chain MHCs under conditions where low levels of agonist single chain p-MHC complexes and high levels of non-stimulatory single chain p-MHC complexes were expressed. Use of this experimental system allowed us to compare CD8+ T cell responses to agonist pMHC in the presence or absence of non-stimulatory pMHC. The protocol describes cell line transfection with single chain MHC constructs, generation of stable cell lines, culture of hepatitis B virus-specific human CD8+ T cells and T cell activation experiments simultaneously quantifying cytokine production and degranulation. The presented methods can be used for research on different aspects of CD8+ T cell activation in human T cell systems with known peptide MHC specificity.

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Mechanisms and Consequences of Antigen Presentation by CD1

Cited by 37 publications

References 119 publications

Synthesis and biological activities of C-glycosides of KRN 7000 with novel ceramide residues

Synthesis and biological activities of C-glycosides of KRN 7000 with novel ceramide residues

Dual immune effect of iNKT cells considering human cutaneous and visceral leishmaniasis: An example of cell plasticity according to different disease scenarios

Use of Single Chain MHC Technology to Investigate Co-agonism in Human CD8+ T Cell Activation

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