Re-programming mouse liver-resident invariant natural killer T cells for suppressing hepatic and diabetogenic autoimmunity.
Channakeshava Sokke UmeshappaPatricia SoléJun YamanouchiSaswat MohapatraBas G J SurewaardJosep GarnicaSantiswarup SinghaDebajyoti MondalElena Cortés-VicenteCharlotte D'MelloAndrew MasonPaul KubesPau SerraYang YangPere SantamariaPublished in: Nature communications (2022)
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 + Maf low Rorc - 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 Zbtb16 high Maf high Tbx21 + 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.
Keyphrases
- induced apoptosis
- cell cycle arrest
- transcription factor
- signaling pathway
- patient safety
- oxidative stress
- gene expression
- endoplasmic reticulum stress
- stem cells
- quality improvement
- type diabetes
- mesenchymal stem cells
- adipose tissue
- metabolic syndrome
- pi k akt
- high frequency
- cell proliferation
- autism spectrum disorder
- heat stress
- insulin resistance
- wild type