A microbiota-responsive polyfunctional cytotoxic CD4+ T-cell state promotes mucosal inflammation in ulcerative colitis

Authors

Thomas, J. P., Kottoor, S. H., Lo, J. W., Wooldridge, T., Ibraheim, H., Digby-Bell, J., Lambie, N., Olbei, M., Bohar, B., Wong, C., Maroof, E., Cao, Y., Baskar, R., Madgwick, M., Cozzetto, D., Kudo, H., Goldin, R., Matthews, N., Korcsmaros, T., Powell, N.

Abstract

Ulcerative colitis (UC) is characterised by chronic colonic inflammation with marked heterogeneity in disease severity and therapeutic outcomes. Here, we define a spatially organised, polyfunctional cytotoxic CD4+ T-cell state associated with mucosal inflammation and adverse therapeutic outcomes in UC. Integrating ex vivo T-cell receptor stimulation with multi-cohort bulk and single-cell transcriptomics and multiparameter flow cytometry, we show that GZMB+ CD4+ T cells are preferentially enriched in inflamed UC mucosa, but not peripheral blood, and co-express cytotoxic molecules, Th1- and Th17-associated cytokines and chemokines, and immunoregulatory receptors. Single-cell analyses implicate inflammatory cytokine and antigen-presentation signals in the acquisition or maintenance of this state. High-resolution spatial profiling localised this programme predominantly to Th17 cells, which were preferentially enriched within multicellular inflammatory and tertiary lymphoid structure-associated niches. Across independent patient cohorts, a transcriptional signature derived from this state increased with endoscopic disease severity and was associated with reduced response to anti-TNF and anti-IL-12/23p40 therapies. Adoptive transfer of Gzma/Gzmb-deficient rather than wild-type CD4+ T cells into Rag2-deficient recipient mice markedly attenuated experimental colitis and abrogated the polyfunctional cytokine phenotype, demonstrating that granzyme-dependent effector activity is a key mechanism driving CD4+ T-cell-mediated intestinal inflammation. Finally, human host-microbiome analysis linked this programme to intestinal dysbiosis, while transfer of dysbiotic microbiota promoted the emergence of a corresponding state in vivo. Collectively, these findings define a microbiota-responsive, spatially organised polyfunctional cytotoxic CD4+ T-cell programme that contributes to intestinal inflammation and is associated with disease severity and treatment resistance in UC.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 15 Aug 2026.

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