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

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 CD44(hi)-CCR7(lo)-CD62L(lo)-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.