Umeshappa, Channakeshava SokkeSolé, PatriciaYamanouchi, JunMohapatra, SaswatSurewaard, Bas G. J.Garnica Caparrós, JosepSingha, SantiswarupMondal, DebajyotiCortés Vicente, ElenaD'Mello, CharlotteMason, AndrewKubes, PaulSerra, PauYang, YangSantamaria, Pere2024-03-272024-03-272022-06-072041-1723https://hdl.handle.net/2445/209280Invariant NKT (iNKT) cells comprise a heterogeneous group of non-circulating, tissue-resident T lymphocytes that recognize glycolipids, including alpha-galactosylceramide (?GalCer), in the context of CD1d, but whether peripheral iNKT cell subsets are terminally differentiated remains unclear. Here we show that mouse and human liver-resident ?GalCer/CD1d-binding iNKTs largely correspond to a novel Zbtb16+Tbx21+Gata3+MaflowRorc- subset that exhibits profound transcriptional, phenotypic and functional plasticity. Repetitive in vivo encounters of these liver iNKT (LiNKT) cells with intravenously delivered ?GalCer/CD1d-coated nanoparticles (NP) trigger their differentiation into immunoregulatory, IL-10+IL-21-producing Zbtb16highMafhighTbx21+Gata3+Rorc- cells, termed LiNKTR1, expressing a T regulatory type 1 (TR1)-like transcriptional signature. This response is LiNKT-specific, since neither lung nor splenic tissue-resident iNKT cells from ?GalCer/CD1d-NP-treated mice produce IL-10 or IL-21. Additionally, these LiNKTR1 cells suppress autoantigen presentation, and recognize CD1d expressed on conventional B cells to induce IL-10+IL-35-producing regulatory B (Breg) cells, leading to the suppression of liver and pancreas autoimmunity. Our results thus suggest that LiNKT cells are plastic for further functional diversification, with such plasticity potentially targetable for suppressing tissue-specific inflammatory phenomena.© 2022. The Author(s).19 p.application/pdfengcc by (c) Umeshappa, Channakeshava Sokke et al., 2022http://creativecommons.org/licenses/by/3.0/es/Malalties autoimmunitàriesCèl·lules TAutoimmune diseasesT cellsinfo:eu-repo/semantics/article2023-06-28info:eu-repo/semantics/openAccess931583035672409