Fatty Acid Oxidation Promotes Apoptotic Resistance and Proinflammatory Phenotype of CD4 Tissue-resident Memory T cells in Crohn's Disease.

Background & Aims: As the most abundant memory T cells and major source of tumor necrosis factor α in the intestinal mucosa of Crohn's disease (CD) patients, CD4 tissue-resident memory T (T) cells play a critical role in CD pathogenesis. We investigated the role of metabolic reprogramming in the regulation of proinflammatory and apoptosis-resistant phenotype for CD4 T cells.

Methods: CD4 T cells were collected from intestinal resection tissues from control and CD patients. Transcriptomic and metabolomic analysis were performed to identify metabolic characteristics of CD4 T cells. Enzyme-linked immunosorbent assay and quantitative polymerase chain reaction experiments were used to assess cytokines level in CD4 T cells; activation-induced cell apoptosis rate was evaluated by flow cytometry. Transwell assay and wound healing assay were performed to detect the effect of CD4 T cells on the migration of normal intestinal epithelial cells.

Results: Transcriptomic data combined with unbiased metabolomic analysis revealed an increased fatty acid oxidation (FAO) phenotype existed in CD4 T cells from CD patients. The lipidomic data and stable isotope tracer experiments demonstrated that CD4 T cells up-regulated their lipid lipolysis and fatty acid uptake to fuel FAO in CD patients. Mechanistically, the activated nuclear factor kappa B signaling increased transcription of genes involved in lipid lipolysis, fatty acid uptake, and oxidation in CD4 T cells from CD patients. Targeting FAO of CD4 T cells reversed their apoptosis-resistant and proinflammatory phenotype in CD patients.

Conclusions: CD4 T cells process an accelerated FAO mediated by activated nuclear factor kappa B signaling in CD patients; targeting FAO could reverse their apoptosis-resistant and proinflammatory phenotype. These findings shed a new light on the pathogenic mechanism investigation and novel therapy development in CD patients.