ABSTRACT
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-18Rlo exclusively identify tissue-resident cells whereas IL-18Rhi population contains both tissue-resident and migratory ones. Local cytokines including transforming growth factor ß (TGF-ß) and interferon α (IFN-α)/ß as well as TGF-ß-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.
ABSTRACT
Tissue-resident memory T (TRM) cells, a population of noncirculating memory T cells, are one of the essential components of immunological memory in both mouse and human. Although CD69+CD103+ TRM cells represent a major TRM cell population in barrier tissues including the mucosal surface and the skin, CD69+CD103- TRM cells dominate most nonbarrier tissues, such as the kidney. TGF-ß is required for the differentiation of CD69+CD103+ TRM cells in barrier tissues. However, the developmental control of CD69+CD103- TRM cells in nonbarrier tissues remains largely unknown and the involvement of TGF-ß signaling is less clear. In this study we demonstrated that TGF-ß promoted the formation of kidney-resident T cells via enhancing the tissue entry of effector T cells. Mechanistically, TGF-ß enhanced E- and P-selectin and inflammatory chemokine-mediated extravasation of effector T cells. Thus TGF-ß controls the first developmental checkpoint of TRM cell differentiation in nonbarrier tissues.
