Identification of a unique subset of tissue-resident memory CD4 ⁺ T cells in Crohn’s disease

<jats:p> T cells differentiate into highly diverse subsets and display plasticity depending on the environment. Although lymphocytes are key mediators of inflammation, functional specialization of T cells in inflammatory bowel disease (IBD) has not been effectively described. Here, we performed deep profiling of T cells in the intestinal mucosa of IBD and identified a CD4 <jats:sup>+</jats:sup> tissue-resident memory T cell (Trm) subset that is increased in Crohn’s disease (CD) showing unique inflammatory properties. Functionally and transcriptionally distinct CD4 <jats:sup>+</jats:sup> Trm subsets are observed in the inflamed gut mucosa, among which a CD-specific CD4 <jats:sup>+</jats:sup> Trm subset, expressing CD161 and CCR5 along with CD103, displays previously unrecognized pleiotropic signatures of innate and effector activities. These inflammatory features are further enhanced by their spatial proximity to gut epithelial cells. Furthermore, the CD-specific CD4 <jats:sup>+</jats:sup> Trm subset is the most predominant producer of type 1 inflammatory cytokines upon various stimulations among all CD4 <jats:sup>+</jats:sup> T cells, suggesting that the accumulation of this T cell subset is a pathological hallmark of CD. Our results provide comprehensive insights into the pathogenesis of IBD, paving the way for decoding of the molecular mechanisms underlying this disease. </jats:p>