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

Low-grade systemic inflammation associated toobesity leads to cardiovascular complications,caused partly by infiltration of adipose and vasculartissue by effector T cells. The signals leading toT cell differentiation and tissue infiltration duringobesity are poorly understood. We tested whethersaturated fatty acid-induced metabolic stress affectsdifferentiation and trafficking patterns of CD4⁺T cells.Memory CD4⁺T cells primed in high-fat diet-fed do-nors preferentially migrated to non-lymphoid, inflam-matory sites, independent of the metabolic status ofthe hosts. This was due to biased CD4⁺T cell differen-tiation 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 observedin obese subjects in a cohort of free-living people. Thisdevelopmental bias was independent of any cross-talk between CD4⁺T cells and dendritic cells andwas mediated via direct exposure of CD4⁺T cells topalmitate, leading to increased activation of a PI3Kp110δ-Akt-dependent pathway upon priming.