The downregulation of IL-18R defines bona fide kidney-resident CD8⁺ T cells

Stepwise induction of CD69 and CD103 marks distinct differentiation stages of mucosal Trms. But the majority of non-mucosal Trm lacks CD103 expression. The expression of CD69 alone cannot faithfully define Trm cells in heavily vascularized non-mucosal tissues, such as the kidney. Here, we found that a subset of kidney Trms downregulated IL-18 receptor during differentiation. Via global transcriptional analysis and parabiosis experiments, we have discovered that the downregulation of interleukin-18 receptor (IL-18R) is associated with the establishment of tissue residency. Together with the expression of CD69, IL-18R^lo exclusively identify tissue-resident cells whereas IL-18R^hi population contains both tissue-resident and migratory ones. Local cytokines including transforming growth factor β (TGF-β) and interferon α (IFN-α)/β as well as TGF-β-dependent suppression of transcription factor Tcf-1 are essential for IL-18R downregulation during kidney Trm differentiation. Together, we identified a convenient surface marker to distinguish bona fide kidney-resident CD8⁺ T cells as well as underlying molecular mechanisms controlling this differentiation process.