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Binding of ligands to CD1 molecules and activation of CD1d restricted iNKT cells

signalling dataset

We have developed structural, kinetic and functional data to study the binding of ligands to CD1 molecules and activation of CD1d restricted iNKT cells. The results of these studies have led to:

i) The development of protocols to refold in vitro CD1 molecules, which were used for the generation of CD1 tetramers. Ability to generate CD1d tetramers has provided us with the opportunity of comparing a broad panel of CD1d binding compounds for their ability to stimulate iNKT cells.

ii) Identification of a novel population of NKT cells, which does not express the canonical invariant Valpha24 / Vbeta11 TCR .

iii) Crystal structures of CD1b molecules loaded with phosphatidylinositol, ganglioside GM2 and glucomonomycolate and more recently of human CD1d loaded with alpha-GalCer.

iv) Crystal structures of canonical and non canonical NKT TCR.

v) Demonstration that stimulation of iNKT cells in vivo with the synthetic CD1d ligand alpha-GalCer significantly enhances immune responses to protein and peptide based vaccines, due to rapid iNKT dependent DC maturation.

vi) We have also described the impact of combining injection of protein vaccines with a combination of iNKT cell-agonist alpha-GalCer and MPL, a detoxified version of LPS that signals through TLR4. This combination treatment stimulates antigen-specific T and B cell responses that are greater than those elicited with alpha-GalCer or MPL alone. Over the next few months we intend to extend these results to a new class of NKT cell agonist, which we have recently described, which are like alpha galactosylceramide have non-glycosidic lipids.

vii) Characterisation of Siglec-H as a novel endocytic receptor expressed on murine plasmacytoid dendritic cell precursors. Siglec-H functioned as an endocytic receptor and mediated efficient internalization of anti-Siglec-H Abs. By immunizing mice with ovalbumin-conjugated anti-Siglec-H Ab in the presence of CpG, we demonstrate generation of antigen-specific CD8 T cells in vivo. Targeting Siglec-H may therefore be a useful way of delivering antigens to pDCs for cross presentation.




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