Work

Immunometabolic Defects in Intestinal CD8+ T Cells Disrupt Epithelial Integrity in treated people with HIV 2309248

Year: 2026

Type: article

Abstract: Introduction The intestinal mucosa requires tightly regulated immune—epithelial metabolic crosstalk to maintain barrier integrity. In people with HIV (PWH) receiving suppressive antiretroviral therapy (ART), persistent gut epithelial damage and inflammation remain unresolved. The mechanisms by which tissue-resident immune cells contribute to epithelial injury in this setting are poorly understood. We hypothesized that immunometabolic dysfunction in intestinal CD8+ T cells drive pathological epithelial remodeling in treated HIV. Methods We analyzed patient-matched colonic biopsies from PWH on ART and HIV-negative controls using transcriptional profiling, metabolic assays, imaging, and functional perturbations. Autologous human intestinal organoid—CD8+ T-cell co-culture systems were used to define immune—epithelial interactions. Pharmacologic modulation of lipid metabolism and PPARγ signaling was performed to assess causality. Results Intestinal CD8+ T cells from PWH exhibited profound lipid depletion and heightened activation compared to peripheral counterparts, independent of HIV antigen specificity. This phenotype was driven by transcriptional repression of the PPARγ lipid-metabolic program. Lipid-deficient CD8+ T cells scavenged plasma membrane fragments from adjacent epithelial cells, inducing epithelial apoptosis and barrier disruption. Restoration of epithelial integrity occurred only with PPARγ agonist treatment, not with nonspecific lipid supplementation, demonstrating a cell-intrinsic requirement for PPARγ-regulated lipid metabolism. Conclusion These findings uncover a previously unrecognized nutrient-signaling axis in which lipid stress in intestinal CD8+ T cells drive epithelial damage in treated HIV. Targeting tissue-resident immunometabolism–specifically the PPARγ—lipid axis–represents a promising therapeutic strategy to restore mucosal barrier homeostasis in HIV and other chronic inflammatory diseases. Funding Source K99 Topic Categories Immune Mechanisms of Human Disease (HUM)

Source: The Journal of Immunology

DOI: 10.1093/jimmun/vkag141.1519