Differential proteomic and metabolic remodelling of CD4⁺ and CD8⁺ T cells in mesenteric lymph nodes during colitis-associated colorectal cancer

Abstract

Patients with colitis are at elevated risk of developing colitis-associated colorectal cancer (CAC), yet the molecular and metabolic adaptations of T cells during this process remain unclear. Using quantitative mass spectrometry in the AOM/DSS mouse model we mapped proteomic networks of CD4+ and CD8+ T cells in mesenteric lymph nodes across healthy, colitis, and cancer stages. CD4 T cells expanded during CAC progression and underwent extensive proteomic remodelling, including upregulation of DNA replication, cell cycle, ribosome biogenesis, and translation. These changes were accompanied by enhanced glycolysis, TCA activity, mitochondrial mass, and oxidative phosphorylation, indicating a highly metabolically active state. In contrast, CD8 T cells showed minimal changes in cell number, protein content and in metabolic and proteomic remodelling. CD4 T cells progressively acquire inflammatory Th1 and regulatory features, whereas CD8 T cells remained poorly activated. Together, these findings reveal distinct T cell adaptations shaped by CAC and identify potential immunometabolic targets.