Benzofuran sulfonates and small self-lipid antigens activate type II NKT cells via CD1d
Almeida, Catarina F; Smith, Dylan G M; Cheng, Tan-Yun; Harpur, Chris M; Batleska, Elena; Nguyen-Robertson, Catriona V; Nguyen, Tram; Thelemann, Tamara; Reddiex, Scott J J; Li, Shihan; Eckle, Sidonia B G; Van Rhijn, Ildiko; Rossjohn, Jamie; Uldrich, Adam P; Moody, D Branch; Williams, Spencer J; Pellicci, Daniel G; Godfrey, Dale I
(2021) Proceedings of the National Academy of Sciences of the United States of America, volume 118, issue 34, pp. 1 - 12
(Article)
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
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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.
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Keywords: Antigen, CD1d, PPBF, TCR, Type II NKT, Taverne, General
ISSN: 0027-8424
Publisher: National Academy of Sciences
Note: Funding Information: ACKNOWLEDGMENTS. We are grateful to Dr. Paul Savage (Brigham Young University, Provo, UT) for providing the α-GalCer analogue PBS44 used for production of CD1d-α-GalCer tetramers. We thank the staff from the flow cytometry facilities at the Department of Microbiology and Immunology at the Peter Doherty Institute and the Melbourne Brain Centre at the University of Melbourne. This work was supported by the Australian Research Council (ARC; DP170104386, DP210100235, and CE140100011), the National Health and Medical Research Council of Australia (NHMRC; 1113293, 1083885, and 1145373), the NIH (R01 AR048632 and AI049313), the Allergy and Immunology Foundation of Australia (C.F.A., 2021), and the University of Melbourne (Early Career Researcher Grant; C.F.A., 2021). S.B.G.E. is supported by ARC Discovery Early Career Research Award Fellowship DE170100407. J.R. is supported by an ARC Australian Laureate Fellowship. A.P.U. was supported by a Future Fellowship (FT140100278). D.G.P. is supported by a CSL Centenary Fellowship. D.I.G. is supported by an NHMRC Senior Principal Research Fellowship (1117766). Funding Information: We are grateful to Dr. Paul Savage (Brigham Young University, Provo, UT) for providing the ?-GalCer analogue PBS44 used for production of CD1d-?-GalCer tetramers. We thank the staff from the flow cytometry facilities at the Department of Microbiology and Immunology at the Peter Doherty Institute and the Melbourne Brain Centre at the University of Melbourne. This work was supported by the Australian Research Council (ARC; DP170104386, DP210100235, and CE140100011), the National Health and Medical Research Council of Australia (NHMRC; 1113293, 1083885, and 1145373), the NIH (R01 AR048632 and AI049313), the Allergy and Immunology Foundation of Australia (C.F.A., 2021), and the University of Melbourne (Early Career Researcher Grant; C.F.A., 2021). S.B.G.E. is supported by ARC Discovery Early Career Research Award Fellowship DE170100407. J.R. is supported by an ARC Australian Laureate Fellowship. A.P.U. was supported by a Future Fellowship (FT140100278). D.G.P. is supported by a CSL Centenary Fellowship. D.I.G. is supported by an NHMRC Senior Principal Research Fellowship (1117766). Publisher Copyright: © 2021 National Academy of Sciences. All rights reserved.
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