Homeostatic Function and Inflammatory Activation of Ileal CD8+ Tissue-Resident T Cells Is Dependent on Mucosal Location

Lisanne Lutter,Britt Roosenboom,Eelco C Brand,José J Ter Linde,Bas Oldenburg,Ellen G Van Lochem,Carmen S Horjus Talabur Horje,Femke Van Wijk

doi:10.1016/j.jcmgh.2021.06.022

Lisanne Lutter, Britt Roosenboom + Show 6 more

Open Access

https://doi.org/10.1016/j.jcmgh.2021.06.022

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Abstract

Background & AimsTissue-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.MethodsHere, 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.ResultsOur 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.ConclusionsAltogether, 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.

Highlights

MethodsWe performed imaging mass cytometry, flow cytometry, and RNA-sequencing to compare lamina propria and intraepithelial CD103þ/–CD69þCD8þ Trm cells in healthy control subjects and patients with active ileal Crohn’s disease
BACKGROUND & AIMSTissue-resident memory T (Trm) cells, both of the CD4 and CD8 lineage, have been implicated in disease flares in inflammatory bowel disease
Our data revealed that lamina propria CD103þCD69þCD8þ T cells have a classical Trm cell profile with active pathways for regulating cell survival/death and cytokine signaling, whereas intraepithelial CD103þCD69þCD8þ T cells display tightly regulated innate-like cytotoxic profile

Summary

Methods

We performed imaging mass cytometry, flow cytometry, and RNA-sequencing to compare lamina propria and intraepithelial CD103þ/–CD69þCD8þ Trm cells in healthy control subjects and patients with active ileal Crohn’s disease. Multiple biopsy specimens were taken for histopathological analysis, for immunophenotyping by flow cytometry analysis (n 1⁄4 27), and for RNA-sequencing of sorted subsets and imaging mass cytometry (n 1⁄4 4). Healthy control subjects (n 1⁄4 10) underwent ileocolonoscopy for polyp surveillance or iron deficiency. They had normal macroscopical ileal mucosa, which was confirmed by histology (see Table 1 for patient characteristics). Biopsies for analysis without separation of the lamina propria and epithelium were stored in a phosphate-buffered saline solution at 2–8C, after which flow cytometric.

Results

Discussion

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