Re-programming mouse liver-resident invariant natural killer T cells for suppressing hepatic and diabetogenic autoimmunity

Channakeshava Sokke Umeshappa, Patricia Solé, Jun Yamanouchi, Saswat Mohapatra, Bas G. J. Surewaard, Josep Garnica, Santiswarup Singha, Debajyoti Mondal, Elena Cortés-Vicente, Charlotte D’Mello, Andrew Mason, Paul Kubes, Pau Serra, Yang Yang and Pere Santamaria ()
Additional contact information
Channakeshava Sokke Umeshappa: Julia McFarlane Diabetes Research Centre and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary
Patricia Solé: Institut D’Investigacions Biomèdiques August Pi i Sunyer
Jun Yamanouchi: Julia McFarlane Diabetes Research Centre and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary
Saswat Mohapatra: Julia McFarlane Diabetes Research Centre and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary
Bas G. J. Surewaard: University of Calgary
Josep Garnica: Institut D’Investigacions Biomèdiques August Pi i Sunyer
Santiswarup Singha: Julia McFarlane Diabetes Research Centre and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary
Debajyoti Mondal: Julia McFarlane Diabetes Research Centre and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary
Elena Cortés-Vicente: Julia McFarlane Diabetes Research Centre and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary
Charlotte D’Mello: Julia McFarlane Diabetes Research Centre and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary
Andrew Mason: University of Alberta
Paul Kubes: University of Calgary
Pau Serra: Institut D’Investigacions Biomèdiques August Pi i Sunyer
Yang Yang: Julia McFarlane Diabetes Research Centre and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary
Pere Santamaria: Julia McFarlane Diabetes Research Centre and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract Invariant NKT (iNKT) cells comprise a heterogeneous group of non-circulating, tissue-resident T lymphocytes that recognize glycolipids, including alpha-galactosylceramide (αGalCer), 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 αGalCer/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 αGalCer/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 αGalCer/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.

Date: 2022
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DOI: 10.1038/s41467-022-30759-w

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