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

Abstract

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_RM) 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_RM cells.

Methods: CD4⁺ T_RM 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_RM cells. Enzyme-linked immunosorbent assay and quantitative polymerase chain reaction experiments were used to assess cytokines level in CD4⁺ T_RM 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_RM 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_RM cells from CD patients. The lipidomic data and stable isotope tracer experiments demonstrated that CD4⁺ T_RM 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_RM cells from CD patients. Targeting FAO of CD4⁺ T_RM cells reversed their apoptosis-resistant and proinflammatory phenotype in CD patients.

Conclusions: CD4⁺ T_RM 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.

Keywords: CD4(+) Tissue-resident Memory T Cell; Crohn’s Disease; Fatty Acid Oxidation; Proinflamatory Phenotype.