A molecular basis for NKT cell recognition of CD1d-self-antigen

Thierry Mallevaey; Andrew J. Clarke; James P. Scott-Browne; Mary H. Young; Laila C. Roisman; Daniel G. Pellicci; Onisha Patel; Julian P. Vivian; Jennifer L. Matsuda; James McCluskey; Dale I. Godfrey; Philippa Marrack; Jamie Rossjohn; Laurent Gapin

doi:10.1016/j.immuni.2011.01.013

A molecular basis for NKT cell recognition of CD1d-self-antigen

Thierry Mallevaey, Andrew J. Clarke, James P. Scott-Browne, Mary H. Young, Laila C. Roisman, Daniel G. Pellicci, Onisha Patel, Julian P. Vivian, Jennifer L. Matsuda, James McCluskey, Dale I. Godfrey, Philippa Marrack, Jamie Rossjohn, Laurent Gapin

Research output: Contribution to journal › Article › peer-review

118 Scopus citations

Abstract

The antigen receptor for natural killer T cells (NKT TCR) binds CD1d-restricted microbial and self-lipid antigens, although the molecular basis of self-CD1d recognition is unclear. Here, we have characterized NKT TCR recognition of CD1d molecules loaded with natural self-antigens (Ags) and report the 2.3 Å resolution structure of an autoreactive NKT TCR-phosphatidylinositol-CD1d complex. NKT TCR recognition of self- and foreign antigens was underpinned by a similar mode of germline-encoded recognition of CD1d. However, NKT TCR autoreactivity is mediated by unique sequences within the non-germline-encoded CDR3β loop encoding for a hydrophobic motif that promotes self-association with CD1d. Accordingly, NKT cell autoreactivity may arise from the inherent affinity of the interaction between CD1d and the NKT TCR, resulting in the recognition of a broad range of CD1d-restricted self-antigens. This demonstrates that multiple self-antigens can be recognized in a similar manner by autoreactive NKT TCRs.

Original language	English
Pages (from-to)	315-326
Number of pages	12
Journal	Immunity
Volume	34
Issue number	3
DOIs	https://doi.org/10.1016/j.immuni.2011.01.013
State	Published - 25 Mar 2011
Externally published	Yes

ASJC Scopus subject areas

Immunology and Allergy
Immunology
Infectious Diseases

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10.1016/j.immuni.2011.01.013

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@article{940d556a80e54e0f803abf1e888749db,

title = "A molecular basis for NKT cell recognition of CD1d-self-antigen",

abstract = "The antigen receptor for natural killer T cells (NKT TCR) binds CD1d-restricted microbial and self-lipid antigens, although the molecular basis of self-CD1d recognition is unclear. Here, we have characterized NKT TCR recognition of CD1d molecules loaded with natural self-antigens (Ags) and report the 2.3 {\AA} resolution structure of an autoreactive NKT TCR-phosphatidylinositol-CD1d complex. NKT TCR recognition of self- and foreign antigens was underpinned by a similar mode of germline-encoded recognition of CD1d. However, NKT TCR autoreactivity is mediated by unique sequences within the non-germline-encoded CDR3β loop encoding for a hydrophobic motif that promotes self-association with CD1d. Accordingly, NKT cell autoreactivity may arise from the inherent affinity of the interaction between CD1d and the NKT TCR, resulting in the recognition of a broad range of CD1d-restricted self-antigens. This demonstrates that multiple self-antigens can be recognized in a similar manner by autoreactive NKT TCRs.",

author = "Thierry Mallevaey and Clarke, {Andrew J.} and Scott-Browne, {James P.} and Young, {Mary H.} and Roisman, {Laila C.} and Pellicci, {Daniel G.} and Onisha Patel and Vivian, {Julian P.} and Matsuda, {Jennifer L.} and James McCluskey and Godfrey, {Dale I.} and Philippa Marrack and Jamie Rossjohn and Laurent Gapin",

note = "Funding Information: This work was supported by National Institutes of Health (AI076463 and AI078246 to L.G. and AI187785 to P.M.), NIH training grant T32 AI07405 to J.P.S.-B. and M.H.Y.; Howard Hughes Medical Institute (P.M.); the Cancer Council of Victoria, and the National Health and Medical Research Council of Australia. D.I.G. is supported by an NHMRC fellowship; J.R. is supported by an Australian Research Council Federation Fellowship. T.M., A.J.C., J.R., and L.G. designed the experiments, did the experimental work, analyzed the experiments, and prepared the manuscript. D.G.P., O.P., J.L.M., M.H.Y., D.I.G., J.M., L.C.R., J.P.V., and P.M. provided intellectual insight and crystallographic data. T.M., J.P.S.-B., D.I.G., P.M., J.R., and L.G. devised the project and wrote the manuscript. ",

year = "2011",

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doi = "10.1016/j.immuni.2011.01.013",

language = "English",

volume = "34",

pages = "315--326",

journal = "Immunity",

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T1 - A molecular basis for NKT cell recognition of CD1d-self-antigen

AU - Mallevaey, Thierry

AU - Clarke, Andrew J.

AU - Scott-Browne, James P.

AU - Young, Mary H.

AU - Roisman, Laila C.

AU - Pellicci, Daniel G.

AU - Patel, Onisha

AU - Vivian, Julian P.

AU - Matsuda, Jennifer L.

AU - McCluskey, James

AU - Godfrey, Dale I.

AU - Marrack, Philippa

AU - Rossjohn, Jamie

AU - Gapin, Laurent

N1 - Funding Information: This work was supported by National Institutes of Health (AI076463 and AI078246 to L.G. and AI187785 to P.M.), NIH training grant T32 AI07405 to J.P.S.-B. and M.H.Y.; Howard Hughes Medical Institute (P.M.); the Cancer Council of Victoria, and the National Health and Medical Research Council of Australia. D.I.G. is supported by an NHMRC fellowship; J.R. is supported by an Australian Research Council Federation Fellowship. T.M., A.J.C., J.R., and L.G. designed the experiments, did the experimental work, analyzed the experiments, and prepared the manuscript. D.G.P., O.P., J.L.M., M.H.Y., D.I.G., J.M., L.C.R., J.P.V., and P.M. provided intellectual insight and crystallographic data. T.M., J.P.S.-B., D.I.G., P.M., J.R., and L.G. devised the project and wrote the manuscript.

PY - 2011/3/25

Y1 - 2011/3/25

N2 - The antigen receptor for natural killer T cells (NKT TCR) binds CD1d-restricted microbial and self-lipid antigens, although the molecular basis of self-CD1d recognition is unclear. Here, we have characterized NKT TCR recognition of CD1d molecules loaded with natural self-antigens (Ags) and report the 2.3 Å resolution structure of an autoreactive NKT TCR-phosphatidylinositol-CD1d complex. NKT TCR recognition of self- and foreign antigens was underpinned by a similar mode of germline-encoded recognition of CD1d. However, NKT TCR autoreactivity is mediated by unique sequences within the non-germline-encoded CDR3β loop encoding for a hydrophobic motif that promotes self-association with CD1d. Accordingly, NKT cell autoreactivity may arise from the inherent affinity of the interaction between CD1d and the NKT TCR, resulting in the recognition of a broad range of CD1d-restricted self-antigens. This demonstrates that multiple self-antigens can be recognized in a similar manner by autoreactive NKT TCRs.

AB - The antigen receptor for natural killer T cells (NKT TCR) binds CD1d-restricted microbial and self-lipid antigens, although the molecular basis of self-CD1d recognition is unclear. Here, we have characterized NKT TCR recognition of CD1d molecules loaded with natural self-antigens (Ags) and report the 2.3 Å resolution structure of an autoreactive NKT TCR-phosphatidylinositol-CD1d complex. NKT TCR recognition of self- and foreign antigens was underpinned by a similar mode of germline-encoded recognition of CD1d. However, NKT TCR autoreactivity is mediated by unique sequences within the non-germline-encoded CDR3β loop encoding for a hydrophobic motif that promotes self-association with CD1d. Accordingly, NKT cell autoreactivity may arise from the inherent affinity of the interaction between CD1d and the NKT TCR, resulting in the recognition of a broad range of CD1d-restricted self-antigens. This demonstrates that multiple self-antigens can be recognized in a similar manner by autoreactive NKT TCRs.

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U2 - 10.1016/j.immuni.2011.01.013

DO - 10.1016/j.immuni.2011.01.013

M3 - Article

C2 - 21376640

AN - SCOPUS:79952752495

SN - 1074-7613

VL - 34

SP - 315

EP - 326

JO - Immunity

JF - Immunity

IS - 3

ER -

A molecular basis for NKT cell recognition of CD1d-self-antigen

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