Photoactivable glycolipid antigens generate stable conjugates with CD1d for invariant Natural Killer T cell activation

Shalu Sharma Kharkwal; Natacha Veerapen; Peter Jervis; Veemal Bhowruth; Amareeta K Besra; Simon J North; Stuart M Haslam; Anne Dell; Judith Hobrath; Padraic Quaid; Patrick Moynihan; Liam Robert Cox; Himanshu Kharkwal; Maurice Zauderer; Gurdyal S Besra; Steven A Porcelli

doi:10.1021/acs.bioconjchem.8b00484

Photoactivable glycolipid antigens generate stable conjugates with CD1d for invariant Natural Killer T cell activation

Shalu Sharma Kharkwal, Natacha Veerapen, Peter Jervis, Veemal Bhowruth, Amareeta K Besra, Simon J North, Stuart M Haslam, Anne Dell, Judith Hobrath, Padraic Quaid, Patrick Moynihan, Liam Robert Cox, Himanshu Kharkwal, Maurice Zauderer, Gurdyal S Besra, Steven A Porcelli

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Abstract

Activation of invariant natural killer T lymphocytes (iNKT cells) by α-galactosylceramide (α-GC) elicits a range of pro-inflammatory or anti-inflammatory immune responses. We report the synthesis and characterization of a series of α-GC analogues with acyl chains of varying length and a terminal benzophenone. These bound efficiently to the glycolipid antigen presenting protein CD1d, and upon photoactivation formed stable CD1d-glycolipid covalent conjugates. Conjugates of benzophenone α-GCs with soluble or cell-bound CD1d proteins retained potent iNKT cell activating properties, with biologic effects that were modulated by acyl chain length and the resulting affinities of conjugates for iNKT cell antigen receptors. Analysis by mass spectrometry identified a unique covalent attachment site for the glycolipid ligands in the hydrophobic ligand binding pocket of CD1d. The creation of covalent conjugates of CD1d with α-GC provides a new tool for probing the biology of glycolipid antigen presentation, as well as opportunities for developing effective immunotherapeutics.

Original language	English
Journal	Bioconjugate Chemistry
Early online date	7 Aug 2018
DOIs	https://doi.org/10.1021/acs.bioconjchem.8b00484
Publication status	E-pub ahead of print - 7 Aug 2018

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Shalu_Sharma_Kharkwal_et_al_Photoactivable_glycolipid_antigens_Bioconjugate_Chemistry_2018
Checked for eligibility: 14/08/2018 This is the accepted manuscript for a forthcoming publication in Bioconjugate Chemistry.
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Kharkwal, S. S., Veerapen, N., Jervis, P., Bhowruth, V., Besra, A. K., North, S. J., Haslam, S. M., Dell, A., Hobrath, J., Quaid, P., Moynihan, P., Cox, L. R., Kharkwal, H., Zauderer, M., Besra, G. S., & Porcelli, S. A. (2018). Photoactivable glycolipid antigens generate stable conjugates with CD1d for invariant Natural Killer T cell activation. Bioconjugate Chemistry. Advance online publication. https://doi.org/10.1021/acs.bioconjchem.8b00484

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title = "Photoactivable glycolipid antigens generate stable conjugates with CD1d for invariant Natural Killer T cell activation",

abstract = "Activation of invariant natural killer T lymphocytes (iNKT cells) by α-galactosylceramide (α-GC) elicits a range of pro-inflammatory or anti-inflammatory immune responses. We report the synthesis and characterization of a series of α-GC analogues with acyl chains of varying length and a terminal benzophenone. These bound efficiently to the glycolipid antigen presenting protein CD1d, and upon photoactivation formed stable CD1d-glycolipid covalent conjugates. Conjugates of benzophenone α-GCs with soluble or cell-bound CD1d proteins retained potent iNKT cell activating properties, with biologic effects that were modulated by acyl chain length and the resulting affinities of conjugates for iNKT cell antigen receptors. Analysis by mass spectrometry identified a unique covalent attachment site for the glycolipid ligands in the hydrophobic ligand binding pocket of CD1d. The creation of covalent conjugates of CD1d with α-GC provides a new tool for probing the biology of glycolipid antigen presentation, as well as opportunities for developing effective immunotherapeutics.",

author = "Kharkwal, {Shalu Sharma} and Natacha Veerapen and Peter Jervis and Veemal Bhowruth and Besra, {Amareeta K} and North, {Simon J} and Haslam, {Stuart M} and Anne Dell and Judith Hobrath and Padraic Quaid and Patrick Moynihan and Cox, {Liam Robert} and Himanshu Kharkwal and Maurice Zauderer and Besra, {Gurdyal S} and Porcelli, {Steven A}",

year = "2018",

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day = "7",

doi = "10.1021/acs.bioconjchem.8b00484",

language = "English",

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publisher = "American Chemical Society",

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Kharkwal, SS, Veerapen, N, Jervis, P, Bhowruth, V, Besra, AK, North, SJ, Haslam, SM, Dell, A, Hobrath, J, Quaid, P, Moynihan, P , Cox, LR, Kharkwal, H, Zauderer, M, Besra, GS & Porcelli, SA 2018, 'Photoactivable glycolipid antigens generate stable conjugates with CD1d for invariant Natural Killer T cell activation', Bioconjugate Chemistry. https://doi.org/10.1021/acs.bioconjchem.8b00484

TY - JOUR

T1 - Photoactivable glycolipid antigens generate stable conjugates with CD1d for invariant Natural Killer T cell activation

AU - Kharkwal, Shalu Sharma

AU - Veerapen, Natacha

AU - Jervis, Peter

AU - Bhowruth, Veemal

AU - Besra, Amareeta K

AU - North, Simon J

AU - Haslam, Stuart M

AU - Dell, Anne

AU - Hobrath, Judith

AU - Quaid, Padraic

AU - Moynihan, Patrick

AU - Cox, Liam Robert

AU - Kharkwal, Himanshu

AU - Zauderer, Maurice

AU - Besra, Gurdyal S

AU - Porcelli, Steven A

PY - 2018/8/7

Y1 - 2018/8/7

N2 - Activation of invariant natural killer T lymphocytes (iNKT cells) by α-galactosylceramide (α-GC) elicits a range of pro-inflammatory or anti-inflammatory immune responses. We report the synthesis and characterization of a series of α-GC analogues with acyl chains of varying length and a terminal benzophenone. These bound efficiently to the glycolipid antigen presenting protein CD1d, and upon photoactivation formed stable CD1d-glycolipid covalent conjugates. Conjugates of benzophenone α-GCs with soluble or cell-bound CD1d proteins retained potent iNKT cell activating properties, with biologic effects that were modulated by acyl chain length and the resulting affinities of conjugates for iNKT cell antigen receptors. Analysis by mass spectrometry identified a unique covalent attachment site for the glycolipid ligands in the hydrophobic ligand binding pocket of CD1d. The creation of covalent conjugates of CD1d with α-GC provides a new tool for probing the biology of glycolipid antigen presentation, as well as opportunities for developing effective immunotherapeutics.

AB - Activation of invariant natural killer T lymphocytes (iNKT cells) by α-galactosylceramide (α-GC) elicits a range of pro-inflammatory or anti-inflammatory immune responses. We report the synthesis and characterization of a series of α-GC analogues with acyl chains of varying length and a terminal benzophenone. These bound efficiently to the glycolipid antigen presenting protein CD1d, and upon photoactivation formed stable CD1d-glycolipid covalent conjugates. Conjugates of benzophenone α-GCs with soluble or cell-bound CD1d proteins retained potent iNKT cell activating properties, with biologic effects that were modulated by acyl chain length and the resulting affinities of conjugates for iNKT cell antigen receptors. Analysis by mass spectrometry identified a unique covalent attachment site for the glycolipid ligands in the hydrophobic ligand binding pocket of CD1d. The creation of covalent conjugates of CD1d with α-GC provides a new tool for probing the biology of glycolipid antigen presentation, as well as opportunities for developing effective immunotherapeutics.

U2 - 10.1021/acs.bioconjchem.8b00484

DO - 10.1021/acs.bioconjchem.8b00484

M3 - Article

C2 - 30085659

SN - 1043-1802

JO - Bioconjugate Chemistry

JF - Bioconjugate Chemistry

ER -

Photoactivable glycolipid antigens generate stable conjugates with CD1d for invariant Natural Killer T cell activation

Abstract

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