The length of lipids bound to human CD1d molecules modulates the affinity of NKT cell TCR and the threshold of NKT cell activation

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 |

Section: Discussionmentioning

confidence: 99%

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

Chancellor

Tocheva

Cave-Ayland

et al. 2017

“…It was shown that the iNKT TCR did not have direct contact with the lipid tails of α-GalCer based on the crystal structure of CD1d-α-GalCeriNKT TCR in mice and in humans (20,21). Nevertheless, a series of analogs with the same glycan head as α-GalCer but with different chain length or presence of double bond on either of the two lipid tails would differ in the binding affinity and dissociation rate for human iNKT TCR when complexed with human CD1d (hCD1d) molecule (22).…”

mentioning

confidence: 99%

Avidity of CD1d-ligand-receptor ternary complex contributes to T-helper 1 (Th1) polarization and anticancer efficacy

Lin

Chang

et al. 2011

Invariant natural killer T cell (NKT) cells (iNKT cells) produce both T-helper 1 (Th1) and T-helper 2 cytokines in response to α-Galactosylceramide (α-GalCer) stimulation and are thought to be the important effectors in the regulation of both innate and adaptive immunity involved in autoimmune disorders, microbial infections, and cancers. However, the anticancer effects of α-GalCer were limited in early clinical trial. In this study, several analogs of α-GalCer, containing phenyl groups in the lipid tails were found to stimulate murine and human iNKT cells to secrete Th1-skewed cytokines and exhibit greater anticancer efficacy in mice than α-GalCer. We explored the possibility of different Vβ usages of murine Vα14 iNKT or human Vα24 iNKT cells, accounting for differential cytokine responses. However, T-cell receptor Vβ analysis revealed no significant differences in Vβ usages by α-GalCer and these phenyl glycolipid analogs. On the other hand, these phenyl glycolipids showed greater binding avidity and stability for iNKT T-cell receptor when complexed with CD1d. These findings suggest that CD1d-phenyl glycolipid complexes may interact with the same population of iNKT cells but with higher avidity and stability to drive Th1 polarization. Thus, this study provides a key to the rational design of Th1 biased CD1d reactive glycolipids in the future.immune-modulating activity | structure | interaction | cancer immunotherapy

“…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).…”

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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

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...