title: Obesity-Induced Metabolic Stress Leads to Biased Effector Memory CD4+T Cell Differentiation via PI3K p110δ-Akt-Mediated Signals.
abstract: Low-grade systemic inflammation associated to obesity leads to cardiovascular complications, caused partly by infiltration of adipose and vascular tissue by effector T cells. The signals leading to T cell differentiation and tissue infiltration during obesity are poorly understood. We tested whether saturated fatty acid-induced metabolic stress affects differentiation and trafficking patterns of CD4+T cells. Memory CD4+T cells primed in high-fat diet-fed donors preferentially migrated to non-lymphoid, inflammatory sites, independent of the metabolic status of the hosts. This was due to biased CD4+T cell differentiation into CD44hi-CCR7lo-CD62Llo-CXCR3+-LFA1+effector memory-like T cells upon priming in high-fat diet-fed animals. Similar phenotype was observed in obese subjects in a cohort of free-living people. This developmental bias was independent of any crosstalk between CD4+T cells and dendritic cells and was mediated via direct exposure of CD4+T cells to palmitate, leading to increased activation of a PI3K p110δ-Akt-dependent pathway upon priming.
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK. Electronic address: c.mauro@qmul.ac.uk.
authors.forename: Claudio
authors.initials: C
authors.lastname: Mauro
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.
authors.forename: Joanne
authors.initials: J
authors.lastname: Smith
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK; Istituto Pasteur, Fondazione Cenci Bolognetti, Rome 00161, Italy.
authors.forename: Danilo
authors.initials: D
authors.lastname: Cucchi
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.
authors.forename: David
authors.initials: D
authors.lastname: Coe
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Fu
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan 9-20133, Italy.
authors.forename: Fabrizia
authors.initials: F
authors.lastname: Bonacina
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan 9-20133, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Baragetti
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan 9-20133, Italy.
authors.forename: Gaia
authors.initials: G
authors.lastname: Cermenati
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan 9-20133, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Caruso
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan 9-20133, Italy.
authors.forename: Nico
authors.initials: N
authors.lastname: Mitro
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan 9-20133, Italy; IRCCS Multimedica, Milan 2-242091, Italy.
authors.forename: Alberico L
authors.initials: AL
authors.lastname: Catapano
authors.affiliation: De Gasperis Cardio Center, Niguarda Ca' Granda Hospital, Milan 3-20162, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Ammirati
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.
authors.forename: Maria P
authors.initials: MP
authors.lastname: Longhi
authors.affiliation: Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, CB22 3AT, UK.
authors.forename: Klaus
authors.initials: K
authors.lastname: Okkenhaug
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan 9-20133, Italy; School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia.
authors.forename: Giuseppe D
authors.initials: GD
authors.lastname: Norata
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK. Electronic address: f.marelli-berg@qmul.ac.uk.
authors.forename: Federica M
authors.initials: FM
authors.lastname: Marelli-Berg
mesh_terms: D050154:Adiposity; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation; D002465:Cell Movement; D003713:Dendritic Cells / Q000276:immunology; D059305:Diet, High-Fat; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D006801:Humans; D007156:Immunologic Memory; D007249:Inflammation / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D008221:Lymphoid Tissue / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D010084:Oxidation-Reduction; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D054367:Receptors, CXCR3 / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological
chemical_list: C515187:CXCR3 protein, human; D005227:Fatty Acids; D054367:Receptors, CXCR3; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt; CD4; T lymphocyte; differentiation; effector memory; high-fat diet; inflammation; obesity; palmitate; saturated fatty acid