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Almeida CF, Smith DGM, Cheng TY, et al. Benzofuran sulfonates and small self-lipid antigens activate type II NKT cells via CD1d. Proc Natl Acad Sci U S A. 2021;118(34)doi: 10.1073/pnas.2104420118.
Almeida, C. F., Smith, D. G. M., Cheng, T. Y., Harpur, C. M., Batleska, E., Nguyen-Robertson, C. V., Nguyen, T., Thelemann, T., Reddiex, S. J. J., Li, S., Eckle, S. B. G., Van Rhijn, I., Rossjohn, J., Uldrich, A. P., Moody, D. B., Williams, S. J., Pellicci, D. G., & Godfrey, D. I. (2021). Benzofuran sulfonates and small self-lipid antigens activate type II NKT cells via CD1d. Proceedings of the National Academy of Sciences of the United States of America, 118(34), . https://doi.org/10.1073/pnas.2104420118
Almeida, Catarina F, et al. "Benzofuran sulfonates and small self-lipid antigens activate type II NKT cells via CD1d." Proceedings of the National Academy of Sciences of the United States of America vol. 118,34 (2021). doi: https://doi.org/10.1073/pnas.2104420118
Almeida CF, Smith DGM, Cheng TY, Harpur CM, Batleska E, Nguyen-Robertson CV, Nguyen T, Thelemann T, Reddiex SJJ, Li S, Eckle SBG, Van Rhijn I, Rossjohn J, Uldrich AP, Moody DB, Williams SJ, Pellicci DG, Godfrey DI. Benzofuran sulfonates and small self-lipid antigens activate type II NKT cells via CD1d. Proc Natl Acad Sci U S A. 2021 Aug 24;118(34). doi: 10.1073/pnas.2104420118. PMID: 34417291; PMCID: PMC8403964.
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Proc Natl Acad Sci U S A. 2021 Aug 24;118(34). doi: 10.1073/pnas.2104420118.

Benzofuran sulfonates and small self-lipid antigens activate type II NKT cells via CD1d.

Proceedings of the National Academy of Sciences of the United States of America

Catarina F Almeida, Dylan G M Smith, Tan-Yun Cheng, Chris M Harpur, Elena Batleska, Catriona V Nguyen-Robertson, Tram Nguyen, Tamara Thelemann, Scott J J Reddiex, Shihan Li, Sidonia B G Eckle, Ildiko Van Rhijn, Jamie Rossjohn, Adam P Uldrich, D Branch Moody, Spencer J Williams, Daniel G Pellicci, Dale I Godfrey

Affiliations

  1. Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia; [email protected] [email protected] [email protected] [email protected] [email protected].
  2. Australian Research Council Centre of Excellence in Advanced Molecular Imaging, The University of Melbourne, Melbourne, VIC 3010, Australia.
  3. School of Chemistry, The University of Melbourne, Melbourne, VIC 3052, Australia.
  4. Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3052, Australia.
  5. Division of Rheumatology, Immunity and Inflammation, Brigham and Women's Hospital, Boston, MA 02115.
  6. Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia.
  7. Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, University Utrecht, 3584CL Utrecht, Netherlands.
  8. Infection and Immunity Program, Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.
  9. Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, VIC 3800, Australia.
  10. Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, United Kingdom.
  11. Division of Rheumatology, Immunity and Inflammation, Brigham and Women's Hospital, Boston, MA 02115; [email protected] [email protected] [email protected] [email protected] [email protected].
  12. Australian Research Council Centre of Excellence in Advanced Molecular Imaging, The University of Melbourne, Melbourne, VIC 3010, Australia; [email protected] [email protected] [email protected] [email protected] [email protected].
  13. Murdoch Children's Research Institute, Parkville, VIC 3052, Australia.
  14. Department of Paediatrics, The University of Melbourne, Parkville, VIC 3052, Australia.

PMID: 34417291 PMCID: PMC8403964 DOI: 10.1073/pnas.2104420118

Abstract

Natural killer T (NKT) cells detect lipids presented by CD1d. Most studies focus on type I NKT cells that express semi-invariant αβ T cell receptors (TCR) and recognize α-galactosylceramides. However, CD1d also presents structurally distinct lipids to NKT cells expressing diverse TCRs (type II NKT cells), but our knowledge of the antigens for type II NKT cells is limited. An early study identified a nonlipidic NKT cell agonist, phenyl pentamethyldihydrobenzofuransulfonate (PPBF), which is notable for its similarity to common sulfa drugs, but its mechanism of NKT cell activation remained unknown. Here, we demonstrate that a range of pentamethylbenzofuransulfonates (PBFs), including PPBF, activate polyclonal type II NKT cells from human donors. Whereas these sulfa drug-like molecules might have acted pharmacologically on cells, here we demonstrate direct contact between TCRs and PBF-treated CD1d complexes. Further, PBF-treated CD1d tetramers identified type II NKT cell populations expressing αβTCRs and γδTCRs, including those with variable and joining region gene usage (TRAV12-1-TRAJ6) that was conserved across donors. By trapping a CD1d-type II NKT TCR complex for direct mass-spectrometric analysis, we detected molecules that allow the binding of CD1d to TCRs, finding that both selected PBF family members and short-chain sphingomyelin lipids are present in these complexes. Furthermore, the combination of PPBF and short-chain sphingomyelin enhances CD1d tetramer staining of PPBF-reactive T cell lines over either molecule alone. This study demonstrates that nonlipidic small molecules, which resemble sulfa drugs implicated in systemic hypersensitivity and drug allergy reactions, are targeted by a polyclonal population of type II NKT cells in a CD1d-restricted manner.

Keywords: CD1d; PPBF; TCR; antigen; type II NKT

Conflict of interest statement

Competing interest statement: D.I.G. is a member of the scientific advisory board for Avalia Immunotherapies, a company that is developing natural killer T cell–based vaccines. I.V.R. and D.B.M. are h

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