title: A bidirectional crosstalk between iNKT cells and adipocytes mediated by leptin modulates susceptibility for T cell mediated hepatitis.
abstract: OBJECTIVE
  Immunometabolism is an emerging field of clinical investigation due to the obesity epidemic worldwide. A reciprocal involvement of immune mediators in the body energy metabolism has been recognized for years, but is only partially understood. We hypothesized that the adipokine leptin could provide an important modulator of iNKT cells.
  
  
  METHODS
  The expression of leptin receptor (LR) on resting and activated iNKT cells was measured by flow cytometry. FACS-sorted hepatic iNKT cells were stimulated with anti-CD3/CD28Ab coated beads in the absence or presence of a neutralizing anti-leptin Ab. Furthermore, we evaluated the outcome of LR blocking nanobody treatment in ConA induced hepatitis and towards metabolic parameters in WT and iNKT cell deficient mice.
  
  
  RESULTS
  The LR is expressed on iNKT cells and leptin suppresses iNKT cell proliferation and cytokine production in vitro. LR deficient iNKT cells are hyper-responsive further enforcing the role of leptin as an important inhibitor of iNKT cell function. Consistently, in vivo blockade of LR signaling exacerbated ConA hepatitis in wild-type but not in iNKT cell deficient mice, through both Janus kinase (JAK)2 and mitogen-activated protein kinase (MAPK) dependent mechanisms. Moreover, LR inhibition altered fat pad features and was accompanied by insulin resistance, only in wild-type mice. Curiously, this interaction was strictly dependent on MAPK mediated LR signaling in iNKT cells and uncoupled from the more central effects of leptin.
  
  
  CONCLUSIONS
  Our data support a new concept of immune regulation by which leptin protects towards T cell mediated hepatitis via modulation of iNKT cells.
authors: Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium.
authors: Koen
authors: K
authors: Venken
authors: Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium.
authors: Sylvie
authors: S
authors: Seeuws
authors: Flanders Institute for Biotechnology, Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Ghent University, A. Baertsoenkaai 3, 9000 Ghent, Belgium.
authors: Lennart
authors: L
authors: Zabeau
authors: Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium.
authors: Peggy
authors: P
authors: Jacques
authors: Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium.
authors: Tine
authors: T
authors: Decruy
authors: Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium.
authors: Julie
authors: J
authors: Coudenys
authors: Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium.
authors: Eveline
authors: E
authors: Verheugen
authors: Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium.
authors: Fien
authors: F
authors: Windels
authors: Flanders Institute for Biotechnology, Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Ghent University, A. Baertsoenkaai 3, 9000 Ghent, Belgium.
authors: Dominiek
authors: D
authors: Catteeuw
authors: Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium.
authors: Michael
authors: M
authors: Drennan
authors: Laboratory for Medicinal Chemistry, Faculty of Pharmaceutical Sciences (FFW), Ghent University, Harelbekestraat 72, 9000 Ghent, Belgium.
authors: Serge
authors: S
authors: Van Calenbergh
authors: Laboratory of Immunoregulation and Mucosal Immunology, Department of Molecular Biomedical Research, VIB and Ghent University, De Pintelaan 185, 9000 Ghent, Belgium.
authors: Bart N
authors: BN
authors: Lambrecht
authors: Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan; Japan Science and Technology Agency, CREST, Tokyo 102-0075, Japan.
authors: Akihiko
authors: A
authors: Yoshimura
authors: Flanders Institute for Biotechnology, Department of Medical Protein Research, Faculty of Medicine and Health Sciences, Ghent University, A. Baertsoenkaai 3, 9000 Ghent, Belgium.
authors: Jan
authors: J
authors: Tavernier
authors: Laboratory for Molecular Immunology and Inflammation, Department of Rheumatology, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium. Electronic address: dirk.elewaut@ugent.be.
authors: Dirk
authors: D
authors: Elewaut
mesh_terms: D017667:Adipocytes / Q000502:physiology*; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D002450:Cell Communication; D004198:Disease Susceptibility; D006505:Hepatitis / Q000209:etiology*; D020738:Leptin / Q000502:physiology*; D008213:Lymphocyte Activation; D020935:MAP Kinase Signaling System; D051379:Mice; D055611:Natural Killer T-Cells / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D054411:Receptors, Leptin / Q000502:physiology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D020738:Leptin; D011948:Receptors, Antigen, T-Cell; D054411:Receptors, Leptin; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins
keywords: ALT; AST; Adipokines; ConA; Immunology; Immunometabolism; LR; Liver pathology; MAPK; SOCS; WAT; alanine aminotransferase; aspartate aminotransferase; concanavalin A; iNKT cell; invariant natural killer T cell; leptin receptor; mAlb; mitogen-activated protein kinase; mouse serum albumin specific nanobody; n.d.; not detectable; suppressor of cytokine signaling; white adipose tissue; α-GalCer; α-galactosylceramide