title: Type II NKT-TFH cells against Gaucher lipids regulate B-cell immunity and inflammation.
abstract: Chronic inflammation including B-cell activation is commonly observed in both inherited (Gaucher disease [GD]) and acquired disorders of lipid metabolism. However, the cellular mechanisms underlying B-cell activation in these settings remain to be elucidated. Here, we report that β-glucosylceramide 22:0 (βGL1-22) and glucosylsphingosine (LGL1), 2 major sphingolipids accumulated in GD, can be recognized by a distinct subset of CD1d-restricted human and murine type II natural killer T (NKT) cells. Human βGL1-22- and LGL1-reactive CD1d tetramer-positive T cells have a distinct T-cell receptor usage and genomic and cytokine profiles compared with the classical type I NKT cells. In contrast to type I NKT cells, βGL1-22- and LGL1-specific NKT cells constitutively express T-follicular helper (TFH) phenotype. Injection of these lipids leads to an increase in respective lipid-specific type II NKT cells in vivo and downstream induction of germinal center B cells, hypergammaglobulinemia, and production of antilipid antibodies. Human βGL1-22- and LGL1-specific NKT cells can provide efficient cognate help to B cells in vitro. Frequency of LGL1-specific T cells in GD mouse models and patients correlates with disease activity and therapeutic response. Our studies identify a novel type II NKT-mediated pathway for glucosphingolipid-mediated dysregulation of humoral immunity and increased risk of B-cell malignancy observed in metabolic lipid disorders.
authors.affiliation: Section of Hematology and.
authors.forename: Shiny
authors.initials: S
authors.lastname: Nair
authors.affiliation: Section of Hematology and.
authors.forename: Chandra Sekhar
authors.initials: CS
authors.lastname: Boddupalli
authors.affiliation: Section of Hematology and.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Verma
authors.affiliation: Section of Digestive Diseases, Department of Medicine, Yale University School of Medicine, New Haven, CT;
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Section of Digestive Diseases, Department of Medicine, Yale University School of Medicine, New Haven, CT;
authors.forename: Ruhua
authors.initials: R
authors.lastname: Yang
authors.affiliation: Department of Neurology and Pediatrics, New York University School of Medicine, New York, NY; and.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Pastores
authors.affiliation: Section of Digestive Diseases, Department of Medicine, Yale University School of Medicine, New Haven, CT; Yale Liver Center and.
authors.forename: Pramod K
authors.initials: PK
authors.lastname: Mistry
authors.affiliation: Section of Hematology and Yale Cancer Center, Yale University School of Medicine, New Haven, CT.
authors.forename: Madhav V
authors.identifier: http://orcid.org/0000-0002-7202-1527
authors.initials: MV
authors.lastname: Dhodapkar
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D005776:Gaucher Disease / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005962:Glucosylceramidase / Q000235:genetics; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics; D007249:Inflammation / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008055:Lipids / Q000009:adverse effects / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000145:classification / Q000502:physiology*; D006377:T-Lymphocytes, Helper-Inducer / Q000145:classification / Q000502:physiology*
chemical_list: D008055:Lipids; D005962:Glucosylceramidase