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

Cell Metab. 2017 Mar 7;25(3):593-609. doi: 10.1016/j.cmet.2017.01.008. Epub 2017 Feb 9.

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.

Keywords: Akt; CD4; T lymphocyte; differentiation; effector memory; high-fat diet; inflammation; obesity; palmitate; saturated fatty acid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adiposity
  • Animals
  • Antigen Presentation / immunology
  • CD4-Positive T-Lymphocytes / immunology*
  • Cell Differentiation*
  • Cell Movement
  • Dendritic Cells / immunology
  • Diet, High-Fat
  • Fatty Acids / metabolism
  • Female
  • Humans
  • Immunologic Memory*
  • Inflammation / pathology
  • Lymphocyte Activation / immunology
  • Lymphoid Tissue / pathology
  • Male
  • Mice, Inbred C57BL
  • Obesity / enzymology
  • Obesity / immunology*
  • Obesity / pathology
  • Oxidation-Reduction
  • Phenotype
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Receptors, CXCR3 / metabolism
  • Signal Transduction*
  • Stress, Physiological*

Substances

  • CXCR3 protein, human
  • Fatty Acids
  • Receptors, CXCR3
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt