Tissue-embedded CD4⁺ plasticity defines mucosal immunity in Inflammatory Bowel Disease
bioRxiv (Cold Spring Harbor Laboratory)
Abstract
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 RORγt⁺ Th population with elevated T-bet expression was linked to progression of inflammation. Moreover, Foxp3⁺ cells co-expressing RORγt 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-bet⁺Granzyme-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. Highlights IBD inflammation shapes CD4 + T-cell plasticity and tissue-residency programming. Correlated CD4 + and cytotoxic CD8 + T cells co-localize in inflamed mucosa. Mucosal CD4⁺ memory T cells show hypo-responsiveness in active IBD. HLA-DR + CD38 + memory CD4⁺ T cells amplify inflammation via cytokine output.
Authors 9
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Leiden University Medical Center
Affiliation as printed
Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Dermatology, Leiden University Medical Center, Leiden, the Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands
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Laura F. Ouboter Aachen Department of Gastroenterology and Hepatology Department of Immunology, Leiden University Medical Center
Leiden University Medical Center
Affiliation as printed
Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands
Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands
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Delft University of Technology
Affiliation as printed
Computer Graphics and Visualization, Delft University of Technology, Delft, the Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands
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Cancer Center Amsterdam · Amsterdam UMC Location Vrije Universiteit Amsterdam
Affiliation as printed
Immunotherapy Center, Cancer Center Amsterdam, Amsterdam UMC location VUmc, Amsterdam, the Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands
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