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The V?14 invariant natural killer T cell TCR forces microbial glycolipids and CD1d into a conserved binding mode.

ABSTRACT: Invariant natural killer T cells (iNKT cells) rapidly produce effector cytokines. In this study, we report the first crystal structures of the iNKT cell T cell receptor (TCR) bound to two natural, microbial glycolipids presented by CD1d. Binding of the TCR induced CDR3-?-dependent structural changes in the F' roof of CD1d; these changes resemble those occurring in the absence of TCR engagement when the highly potent synthetic antigen ?-galactosylceramide (?-GalCer) binds CD1d. Furthermore, in the Borrelia burgdorferi ?-galactosyl diacylglycerol-CD1d complex, TCR binding caused a marked repositioning of the galactose sugar into an orientation that closely resembles ?-GalCer. The TCR-dependent reorientation of the sugar, together with the induced CD1d fit, may explain the weaker potency of the microbial antigens compared with ?-GalCer. We propose that the TCR of iNKT cells binds with a conserved footprint onto CD1d, regardless of the bound glycolipid antigen, and that for microbial antigens this unique binding mode requires TCR-initiated conformational changes.

SUBMITTER: Li Y

PROVIDER: S-EPMC2964572 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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The Vα14 invariant natural killer T cell TCR forces microbial glycolipids and CD1d into a conserved binding mode.

Li Yali Y Girardi Enrico E Wang Jing J Yu Esther Dawen ED Painter Gavin F GF Kronenberg Mitchell M Zajonc Dirk M DM

The Journal of experimental medicine 20101004 11

Invariant natural killer T cells (iNKT cells) rapidly produce effector cytokines. In this study, we report the first crystal structures of the iNKT cell T cell receptor (TCR) bound to two natural, microbial glycolipids presented by CD1d. Binding of the TCR induced CDR3-α-dependent structural changes in the F' roof of CD1d; these changes resemble those occurring in the absence of TCR engagement when the highly potent synthetic antigen α-galactosylceramide (α-GalCer) binds CD1d. Furthermore, in th ...[more]

PMID: 20921281

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Project description:Invariant natural killer T cells recognize glycolipid antigens such as α-galactosylceramide presented by CD1d. In preclinical models of B-cell malignancies, α-galactosylceramide is an adjuvant to tumor vaccination, enhancing tumor-specific T-cell responses and prolonging survival. However, numerical and functional invariant natural killer T-cell defects exist in patients with some cancers. Our aim was to assess this axis in patients with chronic lymphocytic leukemia. The numbers of circulating invariant natural killer T cells and the expression of CD1d on antigen-presenting cells were evaluated in patients with chronic lymphocytic leukemia and age-matched controls. Cytokine profile and in vitro proliferative capacity were determined. Patient- and control-derived invariant natural killer T-cell lines were generated and characterized, and allogeneic and autologous responses to α-galactosylce-ramide-treated leukemia cells were assessed. Absolute numbers and phenotype of invariant natural killer T cells were normal in patients with untreated chronic lymphocytic leukemia, and cytokine profile and proliferative capacity were intact. Chemotherapy-treated patients had reduced numbers of invariant natural killer T cells and myeloid dendritic cells, but α-galactosylceramide-induced proliferation was preserved. Invariant natural killer T-cell lines from patients lysed CD1d-expressing targets. Irradiated α-galactosylceramide-treated leukemic cells elicited allogeneic and autologous invariant natural killer T-cell proliferation, and α-galactosylceramide treatment led to increased proliferation of conventional T cells in response to tumor. In conclusion, the invariant natural killer T-cell and CD1d axis is fundamentally intact in patients with early-stage chronic lymphocytic leukemia and, despite reduced circulating numbers, function is retained in fludarabine-treated patients. Immunotherapies exploiting the adjuvant effect of α-galactosylceramide may be feasible.

Dataset Information

The V?14 invariant natural killer T cell TCR forces microbial glycolipids and CD1d into a conserved binding mode.

Publications

The Vα14 invariant natural killer T cell TCR forces microbial glycolipids and CD1d into a conserved binding mode.

Similar Datasets

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