Obesity-Induced Metabolic Stress Leads to Biased Effector Memory CD4+ T Cell Differentiation via PI3K p110δ-Akt-Mediated Signals

• Published in: Cell metabolism Vol. 25; no. 3; pp. 593 - 609
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.03.2017; Cell Press
• Subjects: Adiposity; Akt; Animals; Antigen Presentation - immunology; CD4; CD4-Positive T-Lymphocytes - immunology; Cell Differentiation; Cell Movement; Dendritic Cells - immunology; Diet, High-Fat; differentiation; effector memory; Fatty Acids - metabolism; Female; high-fat diet; Humans; Immunologic Memory; inflammation; Inflammation - pathology; Lymphocyte Activation - immunology; Lymphoid Tissue - pathology; Male; Mice, Inbred C57BL; obesity; Obesity - enzymology; Obesity - immunology; Obesity - pathology; Oxidation-Reduction; palmitate; Phenotype; Phosphatidylinositol 3-Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Receptors, CXCR3 - metabolism; saturated fatty acid; Signal Transduction; Stress, Physiological; T lymphocyte; saturated fatty acid; CD4; effector memory; differentiation; palmitate; inflammation; high-fat diet; T lymphocyte; Akt; obesity
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2017.01.008

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. [Display omitted] •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.