CD1c Presentation of Synthetic Glycolipid Antigens with Foreign Alkyl Branching Motifs

Jong, Annemieke de; Arce, Eva; Cheng, Tan-Yun; Summeren, Ruben P. van; Feringa, Ben L.; Dudkin, Vadim Y.; Crich, David; Matsunaga, Ichiro; Minnaard, Adriaan J.; Moody, D. Branch

doi:10.1016/j.chembiol.2007.09.010

Cited by 58 publications

(65 citation statements)

References 74 publications

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“…For example, the alkyl chains of Mtb diacylated sulfoglycolipids (AC 2 SGL) govern CD1b-mediated T cell activity, including Cmethyl substituents, stereochemistry and alkyl chain position (39). T cell activation is also sensitive to alkyl chain differences in the CD1c-antigen mannosyl-β-phosphomycoketide (MPM), with length, methyl branching pattern and stereoarrangments influencing responses (40). Furthermore, the length of the alkyl chains and lipid saturation of the CD1d-antigen α-galactosylceramide (α-GalCer) is important for controlling CD1d-restricted invariant NKT cell activity (41).…”

Section: Discussionmentioning

confidence: 99%

CD1b-restricted GEM T cell responses are modulated byMycobacterium tuberculosismycolic acid meromycolate chains

Chancellor

Tocheva

Cave-Ayland

et al. 2017

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

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Tuberculosis, caused by Mycobacterium tuberculosis, remains a major human pandemic. Germline-encoded mycolyl lipid-reactive (GEM) T cells are donor-unrestricted and recognize CD1b-presented mycobacterial mycolates. However, the molecular requirements governing mycolate antigenicity for the GEM T cell receptor (TCR) remain poorly understood. Here, we demonstrate CD1b expression in tuberculosis granulomas and reveal a central role for meromycolate chains in influencing GEM-TCR activity. Meromycolate fine structure influences T cell responses in TB-exposed individuals, and meromycolate alterations modulate functional responses by GEM-TCRs. Computational simulations suggest that meromycolate chain dynamics regulate mycolate head group movement, thereby modulating GEM-TCR activity. Our findings have significant implications for the design of future vaccines that target GEM T cells. Mycobaterium tuberculosis | GEM T cells | CD1b | Mycolate lipids |

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Section: Discussionmentioning

confidence: 99%

CD1b-restricted GEM T cell responses are modulated byMycobacterium tuberculosismycolic acid meromycolate chains

Chancellor

Tocheva

Cave-Ayland

et al. 2017

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

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“…The polar heads of these antigens vary in size from the small carboxylic group of MA to the pentasaccharide of GM1 or potentially larger structures in lipoarabinomannans. Hydrophobic tails, which decisively govern CD1-restricted presentation of some antigens (16,17), also greatly differ in length and structural complexity. For example, up to C 80 long tails, which are not trimmed before presentation (18), compose MA and GMM, whereas short 18:1/16:0 tails are found in GM1.…”

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confidence: 99%

Structural reorganization of the antigen-binding groove of human CD1b for presentation of mycobacterial sulfoglycolipids

Garcia-Alles

Collmann

Versluis

et al. 2011

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

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The mechanisms permitting nonpolymorphic CD1 molecules to present lipid antigens that differ considerably in polar head and aliphatic tails remain elusive. It is also unclear why hydrophobic motifs in the aliphatic tails of some antigens, which presumably embed inside CD1 pockets, contribute to determinants for T-cell recognition. The 1.9-Å crystal structure of an active complex of CD1b and a mycobacterial diacylsulfoglycolipid presented here provides some clues. Upon antigen binding, endogenous spacers of CD1b, which consist of a mixture of diradylglycerols, moved considerably within the lipid-binding groove. Spacer displacement was accompanied by F' pocket closure and an extensive rearrangement of residues exposed to T-cell receptors. Such structural reorganization resulted in reduction of the A' pocket capacity and led to incomplete embedding of the methyl-ramified portion of the phthioceranoyl chain of the antigen, explaining why such hydrophobic motifs are critical for T-cell receptor recognition. Mutagenesis experiments supported the functional importance of the observed structural alterations for T-cell stimulation. Overall, our data delineate a complex molecular mechanism combining spacer repositioning and ligandinduced conformational changes that, together with pocket intricacy, endows CD1b with the required molecular plasticity to present a broad range of structurally diverse antigens.three-dimensional structure | groove shrinking | diacylglycerol endogenous ligand | T lymphocyte activation | CD1b mutant transfectant T lymphocytes have developed the capacity to recognize as antigens a large variety of molecules including peptides, (glyco)lipids, and phosphorylated metabolites (1). Specific recognition of peptides or lipids by T-cell receptors (TCR) occurs when these molecules form antigenic complexes with dedicated antigen-presenting molecules belonging to MHC or CD1 families, respectively. Diversity has forced the immune system to develop appropriate strategies to present antigens in immunogenic form. Polymorphic MHC molecules cope with the peptide repertoire by constraining the ligand conformational space (2). Less clear is how the immune system adapts to the large glycolipid antigenic range and forms antigenic complexes using the functionally nonpolymorphic CD1 molecules.Human antigen-presenting cells (APC) display the CD1a, CD1b, CD1c, and CD1d proteins on their plasma membranes (1, 3). CD1 ectodomains consist of a heavy chain, which folds into three extracellular domains (α1-α3) noncovalently associated with β2-microglobulin (4). Antigen-binding grooves nestle between the α1 and α2 domains and are mostly lined by hydrophobic residues. This allows the antigenic lipids to be anchored via their hydrophobic chains, so that polar motifs protrude toward the aqueous milieu. Consequently, polar heads but not hydrophobic tails are assumed to establish stimulatory contacts with TCRs. Nevertheless, modifications in the lipid chains may also indirectly impact on TCR recognition (5).The number, shape, and conn...

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“…, glucose monomycolate (GMM) (7), glycerol monomycolate (GroMM) (8), diacylated sulfoglycolipids (Ac 2 SGL) (9), mannosyl-␤-1-phosphomycoketide (MPM) (10,11), lipoglycans (lipoarabinomannan and lipomannan) (12), and lipopeptides (13).…”

mentioning

confidence: 99%

“…Synthetic MPM analogs were prepared, incorporating polyprenyl chains where the length and absolute configurations of the C-methyl-branched carbons had been modified and used to stimulate specific T cells. It was concluded that the length, the methyl branching pattern, and the stereochemistry of the polyketide chain control the T cells response (11). Whether this effect was related to differences in lipid intracellular trafficking, CD1c loading, TCR recognition, or a combination of these biological aspects is still not fully understood.…”

mentioning

confidence: 99%

Fatty Acyl Structures of Mycobacterium tuberculosis Sulfoglycolipid Govern T Cell Response

Guiard

Collmann

Garcia-Alles

et al. 2009

The Journal of Immunology

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CD1b-restricted T lymphocytes recognize a large diversity of mycobacterial lipids, which differ in their hydrophilic heads and the structure of their acyl appendages. Both moieties participate in the antigenicity of lipid Ags, but the structural constraints governing binding to CD1b and generation of antigenic CD1b:lipid Ag complexes are still poorly understood. Here, we investigated the structural requirements conferring antigenicity to Mycobacterium tuberculosis sulfoglycolipid Ags using a combination of CD1b:lipid binding and T cell activation assays with both living dendritic cells and plate-bound recombinant soluble CD1b. Comparison of the antigenicity of a panel of synthetic analogs, sharing the same trehalose-sulfate polar head, but differing in the structure of their acyl tails, shows that the number of C-methyl substituents on the fatty acid, the configuration of the chiral centers, and the respective localization of the two different acyl chains on the sugar moiety govern TCR recognition and T lymphocyte activation. These studies have major implications for the design of sulfoglycolipid analogs with potential use as tuberculosis subunit vaccines.

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CD1c Presentation of Synthetic Glycolipid Antigens with Foreign Alkyl Branching Motifs

Cited by 58 publications

References 74 publications

CD1b-restricted GEM T cell responses are modulated byMycobacterium tuberculosismycolic acid meromycolate chains

CD1b-restricted GEM T cell responses are modulated byMycobacterium tuberculosismycolic acid meromycolate chains

Structural reorganization of the antigen-binding groove of human CD1b for presentation of mycobacterial sulfoglycolipids

Fatty Acyl Structures of Mycobacterium tuberculosis Sulfoglycolipid Govern T Cell Response

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