1. Obesity-Induced Metabolic Stress Leads to Biased Effector Memory CD4+ T Cell Differentiation via PI3K p110δ-Akt-Mediated Signals
- Author
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Mauro, Claudio, Smith, Joanne, Cucchi, Danilo, Coe, David, Fu, Hongmei, Bonacina, Fabrizia, Baragetti, Andrea, Cermenati, Gaia, Caruso, Donatella, Mitro, Nico, Catapano, Alberico L, Ammirati, Enrico, Longhi, Maria P, Okkenhaug, Klaus, Norata, Giuseppe D, Marelli-Berg, Federica M, Okkenhaug, Klaus [0000-0002-9432-4051], and Apollo - University of Cambridge Repository
- Subjects
CD4-Positive T-Lymphocytes ,Male ,obesity ,Receptors, CXCR3 ,Physiology ,Lymphoid Tissue ,T-Lymphocytes ,Diet, High-Fat ,Lymphocyte Activation ,Article ,Phosphatidylinositol 3-Kinases ,Cell Movement ,Stress, Physiological ,T lymphocyte ,Animals ,Humans ,effector memory ,Molecular Biology ,Adiposity ,Inflammation ,Antigen Presentation ,Akt ,saturated fatty acid ,Fatty Acids ,Cell Differentiation ,Cell Biology ,differentiation ,Dendritic Cells ,Dietary Fats ,CD4 ,Mice, Inbred C57BL ,high-fat diet ,Phenotype ,palmitate ,Female ,Immunologic Memory ,Oxidation-Reduction ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
Summary 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., Graphical Abstract, Highlights • High-fat diet causes development of inflammatory effector memory CD4+ T cells • A PI3K p110δ-Akt-dependent pathway is key to this CD4+ developmental bias • This pathway is induced by direct exposure of CD4+ T cells to palmitate • CD4+ developmental bias is corrected by inactivation of PI3K p110δ-Akt pathway, Lymphocyte infiltration of non-lymphoid tissues, including adipose and vascular tissues, is a prominent feature of chronic inflammation in diet obesity. Mauro et al. find that the saturated fatty-acid palmitate activates a PI3K p110δ-Akt pathway leading to CD4+ T cell differentiation into effector memory-like T cells upon priming in obese mice and humans.
- Published
- 2018
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