Homeostatic function and inflammatory activation of ileal CD8+ tissue-resident T cells is dependent on mucosal location

Background & Aims: Tissue-resident memory T (Trm) cells, both of the CD4 and CD8 lineage, have been implicated in disease flares in inflammatory bowel disease. However, data are conflicting regarding the profile of human CD8 ⁺ Trm cells, with studies suggesting both proinflammatory and regulatory functions. It is crucial to understand the functional profile of these cells in the context of (new) therapeutic strategies targeting (trafficking of) gut Trm cells. Methods: Here, we performed imaging mass cytometry, flow cytometry, and RNA-sequencing to compare lamina propria and intraepithelial CD103 ^+/–CD69 ⁺CD8 ⁺ Trm cells in healthy control subjects and patients with active ileal Crohn's disease. Results: Our data revealed that lamina propria CD103 ⁺CD69 ⁺CD8 ⁺ T cells have a classical Trm cell profile with active pathways for regulating cell survival/death and cytokine signaling, whereas intraepithelial CD103 ⁺CD69 ⁺CD8 ⁺ T cells display tightly regulated innate-like cytotoxic profile. Furthermore, within lamina propria CD8 ⁺CD103 ^– Trm cells, an Itgb2 ⁺GzmK ⁺KLRG1 ⁺ population distinct from CD103 ⁺ CD8 ⁺ Trm cells is found. During chronic inflammation, especially intraepithelial CD103 ⁺CD69 ⁺CD8 ⁺ T cells displayed an innate proinflammatory profile with concurrent loss of homeostatic functions. Conclusions: Altogether, these compartmental and inflammation-induced differences indicate that therapeutic strategies could have a different impact on the same immune cells depending on the local compartment and presence of an inflammatory milieu, and should be taken into account when investigating short- and long-term effects of new gut T cell–targeting drugs.