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Type II natural killer T cells use features of both innate-like and conventional T cells to recognize sulfatide self antigens

Nature Immunology volume 13, pages 851–856 (2012)Cite this article

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Abstract

Glycolipids presented by the major histocompatibility complex (MHC) class I homolog CD1d are recognized by natural killer T cells (NKT cells) characterized by either a semi-invariant T cell antigen receptor (TCR) repertoire (type I NKT cells or iNKT cells) or a relatively variable TCR repertoire (type II NKT cells). Here we describe the structure of a type II NKT cell TCR in complex with CD1d-lysosulfatide. Both TCR α-chains and TCR β-chains made contact with the CD1d molecule with a diagonal footprint, typical of MHC-TCR interactions, whereas the antigen was recognized exclusively with a single TCR chain, similar to the iNKT cell TCR. Type II NKT cell TCRs, therefore, recognize CD1d-sulfatide complexes by a distinct recognition mechanism characterized by the TCR-binding features of both iNKT cells and conventional peptide-reactive T cells.

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Figure 1: Overall structure and docking orientation of the Hy19.3 TCR on the mouse CD1d–LSF complex.
Figure 2: The CD1d-antigen-TCR interface.
Figure 3: Effect of TCR substitutions on binding affinity.
Figure 4: Substitution of CD1d residues at the interface affects activation of the Hy19.3 hybridoma.
Figure 5: Recognition of self lipids by the Hy19.3 TCR.
Figure 6: Flexibility in the CDR loops of the Hy19.3 TCR.

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NCBI Reference Sequence

Protein Data Bank

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Protein Data Bank

References

  1. Godfrey, D.I., Macdonald, H.R., Kronenberg, M., Smyth, M.J. & Van Kaer, L. NKT cells: what's in a name? Nat. Rev. Immunol. 4, 231–237 (2004).

    CAS  PubMed  Google Scholar 

  2. Godfrey, D.I., Rossjohn, J. & Mccluskey, J. The fidelity, occasional promiscuity, and versatility of T cell receptor recognition. Immunity 28, 304–314 (2008).

    Article  CAS  PubMed  Google Scholar 

  3. Zajonc, D. & Wilson, I.A. Architecture of CD1 proteins. Curr. Top. Microbiol. Immunol. 314, 27–50 (2007).

    CAS  PubMed  Google Scholar 

  4. Borg, N.A. et al. CD1d-lipid-antigen recognition by the semi-invariant NKT T-cell receptor. Nature 448, 44–49 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Pellicci, D.G. et al. Recognition of β-linked self glycolipids mediated by natural killer T cell antigen receptors. Nat. Immunol. 12, 827–833 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Yu, E.D., Girardi, E., Wang, J. & Zajonc, D. Cutting edge: structural basis for the recognition of β-linked glycolipid antigens by invariant NKT cells. J. Immunol. 187, 2079–2083 (2011).

    Article  CAS  PubMed  Google Scholar 

  7. Li, Y. et al. The Vα14 invariant natural killer T cell TCR forces microbial glycolipids and CD1d into a conserved binding mode. J. Exp. Med. 207, 2383–2393 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Pellicci, D.G. et al. Differential recognition of CD1d-α-galactosyl ceramide by the Vβ8.2 and Vβ7 semi-invariant NKT T cell receptors. Immunity 31, 47–59 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kawano, T. et al. CD1d-restricted and TCR-mediated activation of vα14 NKT cells by glycosylceramides. Science 278, 1626–1629 (1997).

    Article  CAS  PubMed  Google Scholar 

  10. Cardell, S. et al. CD1-restricted CD4+ T cells in major histocompatibility complex class II-deficient mice. J. Exp. Med. 182, 993–1004 (1995).

    Article  CAS  PubMed  Google Scholar 

  11. Park, S.H. et al. The mouse CD1d-restricted repertoire is dominated by a few autoreactive T cell receptor families. J. Exp. Med. 193, 893–904 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Exley, M.A. et al. A major fraction of human bone marrow lymphocytes are Th2-like CD1d-reactive T cells that can suppress mixed lymphocyte responses. J. Immunol. 167, 5531–5534 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. Exley, M.A. et al. Cutting edge: compartmentalization of Th1-like noninvariant CD1d-reactive T cells in hepatitis C virus-infected liver. J. Immunol. 168, 1519–1523 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Fuss, I.J. et al. Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis. J. Clin. Invest. 113, 1490–1497 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Jahng, A. et al. Prevention of autoimmunity by targeting a distinct, noninvariant CD1d-reactive T cell population reactive to sulfatide. J. Exp. Med. 199, 947–957 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Terabe, M. & Berzofsky, J.A. NKT cells in immunoregulation of tumor immunity: a new immunoregulatory axis. Trends Immunol. 28, 491–496 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Arrenberg, P., Maricic, I. & Kumar, V. Sulfatide-mediated activation of type II natural killer T cells prevents hepatic ischemic reperfusion injury in mice. Gastroenterology 140, 646–655 (2011).

    Article  CAS  PubMed  Google Scholar 

  18. Yang, S.H. et al. Sulfatide-reactive natural killer T cells abrogate ischemia-reperfusion injury. J. Am. Soc. Nephrol. 22, 1305–1314 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Halder, R.C., Aguilera, C., Maricic, I. & Kumar, V. Type II NKT cell-mediated anergy induction in type I NKT cells prevents inflammatory liver disease. J. Clin. Invest. 117, 2302–2312 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Subramanian, L. et al. NKT cells stimulated by long fatty acyl chain sulfatides protect against type 1 diabetes in nonobese diabetic mice. PLoS ONE 7, e377771 (2012).

    Google Scholar 

  21. Arrenberg, P., Halder, R., Dai, Y., Maricic, I. & Kumar, V. Oligoclonality and innate-like features in the TCR repertoire of type II NKT cells reactive to a β-linked self-glycolipid. Proc. Natl. Acad. Sci. USA 107, 10984–10989 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Roy, K.C. et al. Involvement of secretory and endosomal compartments in presentation of an exogenous self-glycolipid to type II NKT cells. J. Immunol. 180, 2942–2950 (2008).

    Article  CAS  PubMed  Google Scholar 

  23. Blomqvist, M. et al. Multiple tissue-specific isoforms of sulfatide activate CD1d-restricted type II NKT cells. Eur. J. Immunol. 39, 1726–1735 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Toda, K. et al. Lysosulfatide (sulfogalactosylsphingosine) accumulation in tissues from patients with metachromatic leukodystrophy. J. Neurochem. 55, 1585–1591 (1990).

    Article  CAS  PubMed  Google Scholar 

  25. López-Sagaseta, J., Sibener, L.V., Kung, J.E., Gumperz, J. & Adams, E.J. Lysophospholipid presentation by CD1d and recognition by a human natural killer T-cell receptor. EMBO J. 31, 2047–2059 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Rudolph, M.G., Stanfield, R.L. & Wilson, I.A. How TCRs bind MHCs, peptides, and coreceptors. Annu. Rev. Immunol. 24, 419–466 (2006).

    Article  CAS  PubMed  Google Scholar 

  27. Garcia, K.C. et al. An alphabeta T cell receptor structure at 2.5 A and its orientation in the TCR-MHC complex. Science 274, 209–219 (1996).

    Article  CAS  PubMed  Google Scholar 

  28. Hahn, M., Nicholson, M.J., Pyrdol, J. & Wucherpfennig, K.W. Unconventional topology of self peptide-major histocompatibility complex binding by a human autoimmune T cell receptor. Nat. Immunol. 6, 490–496 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Marrack, P., Scott-Browne, J.P., Dai, S., Gapin, L. & Kappler, J.W. Evolutionarily conserved amino acids that control TCR-MHC interaction. Annu. Rev. Immunol. 26, 171–203 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Joyce, S., Girardi, E. & Zajonc, D. NKT cell ligand recognition logic: molecular basis for a synaptic duet and transmission of inflammatory effectors. J. Immunol. 187, 1081–1089 (2011).

    Article  CAS  PubMed  Google Scholar 

  31. Matulis, G. et al. Innate-like control of human iNKT cell autoreactivity via the hypervariable CDR3beta loop. PLoS Biol. 8, e1000402 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Zimmer, M.I. et al. Polymorphisms in CD1d affect antigen presentation and the activation of CD1d-restricted T cells. Proc. Natl. Acad. Sci. USA 106, 1909–1914 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zajonc, D. et al. Structural basis for CD1d presentation of a sulfatide derived from myelin and its implications for autoimmunity. J. Exp. Med. 202, 1517–1526 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Shin, J.H. et al. Mutation of a positively charged cytoplasmic motif within CD1d results in multiple defects in antigen presentation to NKT cells. J. Immunol. 188, 2235–2243 (2012).

    Article  CAS  PubMed  Google Scholar 

  35. Cantu, C., Benlagha, K., Savage, P.B., Bendelac, A. & Teyton, L. The paradox of immune molecular recognition of α-galactosylceramide: low affinity, low specificity for CD1d, high affinity for αβ TCRs. J. Immunol. 170, 4673–4682 (2003).

    Article  CAS  PubMed  Google Scholar 

  36. Ely, L.K. et al. Disparate thermodynamics governing T cell receptor-MHC-I interactions implicate extrinsic factors in guiding MHC restriction. Proc. Natl. Acad. Sci. USA 103, 6641–6646 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Adams, J.J. et al. T cell receptor signaling is limited by docking geometry to peptide-major histocompatibility complex. Immunity 35, 681–693 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Yu, E.D. et al. Structural basis for the recognition of C20:2-αGalCer by the invariant natural killer T cell receptor-like antibody L363. J. Biol. Chem. 287, 1269–1278 (2012).

    Article  CAS  PubMed  Google Scholar 

  39. Wang, J. et al. Lipid binding orientation within CD1d affects recognition of Borrelia burgorferi antigens by NKT cells. Proc. Natl. Acad. Sci. USA 107, 1535–1540 (2010).

    Article  CAS  PubMed  Google Scholar 

  40. Winn, M.D. et al. Overview of the CCP4 suite and current developments. Acta Crystallogr. D Biol. Crystallogr. 67, 235–242 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. McCoy, A.J. et al. Phaser crystallographic software. J. Appl. Crystallogr. 40, 658–674 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Adams, P.D. et al. PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr. D Biol. Crystallogr. 66, 213–221 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Emsley, P., Lohkamp, B., Scott, W.G. & Cowtan, K. Features and development of Coot. Acta Crystallogr. D Biol. Crystallogr. 66, 486–501 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Burdin, N. et al. Structural requirements for antigen presentation by mouse CD1. Proc. Natl. Acad. Sci. USA 97, 10156–10161 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Girardi, E. et al. Unique interplay between sugar and lipid in determining the antigenic potency of bacterial antigens for NKT cells. PLoS Biol. 9, e1001189 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank the Stanford Synchrotron Radiation Lightsource (beamline 7-1) and the Advanced Light Source (beamline 5.0.3) for support during remote collection of data; M. Kronenberg (La Jolla Institute for Allergy & Immunology) for several CD1d mutants; R. Stanfield (The Scripps Research Institute) for computer scripts used for the measurement of docking angles; and N. Vu and J. Nourblin (La Jolla Institute for Allergy & Immunology) for help during cloning and protein expression. Supported by the US National Institutes of Health (AI074952 to D.M.Z. and CA100660 to V.K.), the Juvenile Diabetes Research Foundation (V.K.) and the Multiple Sclerosis National Research Institute (V.K.).

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Authors and Affiliations

  1. Division of Cell Biology, La Jolla Institute for Allergy & Immunology, La Jolla, California, USA

    Enrico Girardi, Jing Wang, Thien-Thi Mac, Pooja Iyer & Dirk M Zajonc

  2. Laboratory of Autoimmunity, Torrey Pines Institute for Molecular Studies, San Diego, California, USA

    Igor Maricic & Vipin Kumar

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  1. Enrico Girardi
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Contributions

E.G. generated the TCR constructs, purified and crystallized the proteins, determined the structures and did surface plasmon resonance experiments; I.M. did the antigen-presentation assays; J.W. and P.I. provided assistance with mutant generation and protein purification; T.-T.M. sequenced the TCR; and E.G., V.K. and D.M.Z. analyzed the data and wrote the manuscript.

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Correspondence to Vipin Kumar or Dirk M Zajonc.

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Girardi, E., Maricic, I., Wang, J. et al. Type II natural killer T cells use features of both innate-like and conventional T cells to recognize sulfatide self antigens. Nat Immunol 13, 851–856 (2012). https://doi.org/10.1038/ni.2371

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