A molecular basis for the exquisite CD1d-restricted antigen specificity and functional responses of natural killer T cells

KS Wun; G Cameron; O Patel; SS Pang; DG Pellicci; LC Sullivan; S Keshipeddy; MH Young; AP Uldrich; MS Thakur; SK Richardson; AR Howell; PA Illarionov; AG Brooks; GS Besra; J McCluskey; L Gapin; SA Porcelli; DI Godfrey; J Rossjohn

Journal article

A molecular basis for the exquisite CD1d-restricted antigen specificity and functional responses of natural killer T cells

KS Wun, G Cameron, O Patel, SS Pang, DG Pellicci, LC Sullivan, S Keshipeddy, MH Young, AP Uldrich, MS Thakur, SK Richardson, AR Howell, PA Illarionov, AG Brooks, GS Besra, J McCluskey, L Gapin, SA Porcelli, DI Godfrey, J Rossjohn

Immunity | Published : 2011

DOI: 10.1016/j.immuni.2011.02.001

Abstract

Natural killer T (NKT) cells respond to a variety of CD1d-restricted antigens (Ags), although the basis for Ag discrimination by the NKT cell receptor (TCR) is unclear. Here we have described NKT TCR fine specificity against several closely related Ags, termed altered glycolipid ligands (AGLs), which differentially stimulate NKT cells. The structures of five ternary complexes all revealed similar docking. Acyl chain modifications did not affect the interaction, but reduced NKT cell proliferation, indicating an affect on Ag processing or presentation. Conversely, truncation of the phytosphingosine chain caused an induced fit mode of TCR binding that affected TCR affinity. Modifications in the..

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University of Melbourne Researchers

Onisha Patel Author

Daniel Pellicci Author

Lucy Sullivan Author

Adam Uldrich Author

Grants

Awarded by National Institutes of Health

Funding Acknowledgements

We thank the staff at the Australian synchrotron for assistance with data collection. We also thank D. Taylor, S. Chakravarti, and K. Field for assistance. We are grateful to P. Savage for generously providing alpha-GalCer (PBS44) for CD1d tetramer loading. This work was supported by the Cancer Council of Victoria, the National Health and Medical Research Council of Australia (NHMRC), and the Australian Research Council. G.C. is supported by CRI predoctoral scholarship and L.C.S. by an NHMRC RD Wright Fellowship. SAP. was supported by NIH grant AI45889. A.R.H. was supported by NIH grant R01GM087136. L.G. is supported by NIH grants (AI076463 and AI078246) and M.H.Y. by NIH training grant T32 AI07405. D.I.G. is supported by an NHMRC Principal Research Fellowship; J.R. is supported by an ARC Federation Fellowship. S.A.P. has received payments as a consultant for Vaccinex, Inc. (Rochester, NY) for work related to the development of therapeutics based on CD1d-pretreated glycolipids.