CD74⁺CCL5⁺ effector CD8⁺ T cells drive mucosal inflammation and predict biologics response in inflammatory bowel...

Inflammatory bowel disease (IBD) exhibits heterogeneous mucosal inflammation and variable responses to biologics therapy. This study aimed to identify the immune cell subsets and molecular programs driving disease pathogenesis and to develop predictive biomarkers for therapeutic outcomes.

We integrated single-cell RNA sequencing, bulk transcriptomic deconvolution, GWAS-based Mendelian randomization, and gut microbiome profiling across multiple IBD cohorts. Immune-microbial interactions were systematically characterized and linked with clinical phenotypes and treatment response. Immunohistochemistry was performed on colonic tissues from 12 IBD patients and 10 healthy controls to validate CCL5 and CD8 + T cell expression. Flow cytometric analysis of peripheral blood samples from 7 IBD patients and 12 healthy individuals was conducted to assess circulating CCL5 + CD8 + T cell proportions.

CCL5 + effector CD8 + T cells emerged as key mediators of colonic inflammation, displaying high IFN-γ/TNF activity and RUNX3/NF-κB-coordinated transcriptional programs. Immunohistochemical validation demonstrated profoundly elevated CCL5 expression (median 4.170% vs. 0.3450%, P < 0.0001) and CD8 + T cell infiltration (median 2.025% vs. 0.2150%, P < 0.0001) in IBD colonic tissues. Peripheral blood showed modest trends toward increased CCL5 + CD8 + T cells, though far less pronounced than tissue changes. Tissue-resident effector CD8 + T cell abundance correlated with disease severity and infliximab resistance. Six causally associated genes (DMAJCI, RMF167, SPRY1, ZFP96, FKBP11, SELPLG) formed a predictive signature for diagnosis and treatment response. Microbiome analyses revealed disrupted networks and immune-microbiome coupling.

CCL5 + CD8 + T cells are profoundly enriched in IBD colonic tissues and drive mucosal inflammation through pro-inflammatory pathways. A six-gene model, particularly involving FKBP11, demonstrated potential for disease stratification and infliximab response prediction. These findings highlight immune and microbial features of IBD that merit further functional and clinical validation.