Tissue-embedded CD4⁺ plasticity defines mucosal immunity in Inflammatory Bowel Disease

Abstract

CD4 T helper (Th) cell responses to commensal microbiota are linked to Inflammatory Bowel Disease (IBD), yet how Th programs coexist and evolve in human tissues remains poorly defined. Here, we profiled CD4 memory T cells in intestinal biopsies using immunological and histological approaches to map their phenotypes, functional states, and spatial relationships across disease states. A marked expansion of CD4 T cells concomitant with a ROR{gamma}t Th population with elevated T-bet expression was linked to progression of inflammation. Moreover, Foxp3 cells co-expressing ROR{gamma}t emerged within the inflamed niche, indicating regulatory-Th17 plasticity. Trajectory visualization revealed a potential branched differentiation path towards either regulatory or tissue-resident Th17-like fates, with both termini expressing activation and proliferation markers. Correlation network analysis connected pro-inflammatory CD4 states to T-betGranzyme-B CD8 subsets, indicative of crosstalk between helper and cytotoxic lineages. Histology corroborated this organization, showing frequent interactions between CD4 and CD8 cells in the lamina propria and epithelial border. In functional assays, TCR stimulation during active disease revealed broad suppression of CD4 pro-inflammatory cytokines concomitant with expansion of Foxp3 cells. Conversely, HLA-DR+CD38+ memory subset retained multifunctionality, producing elevated levels of pro-inflammatory cytokines. Together, these results provide insight into a dynamic, tissue-embedded CD4 landscape in IBD. HighlightsO_LIIBD inflammation shapes CD4+ T-cell plasticity and tissue-residency programming. C_LIO_LICorrelated CD4+ and cytotoxic CD8+ T cells co-localize in inflamed mucosa. C_LIO_LIMucosal CD4 memory T cells show hypo-responsiveness in active IBD. C_LIO_LIHLA-DR+CD38+ memory CD4 T cells amplify inflammation via cytokine output. C_LI