CCR8 expression defines tissue-resident memory T cells in human skin

Human skin harbors two major T cell compartments of equal size that are distinguished by expression of the chemokine receptor CCR8. In vitro studies have demonstrated that CCR8 expression is under strict control of T cell antigen receptor (TCR)-engagement and the skin tissue microenvironment. We here examined the relationship between CCR8+ and CCR8− T cells. Phenotypic, functional, and transcriptomic analyses revealed that CCR8+ skin T cells bear all the hallmarks of resident memory T (TRM) cells, including homeostatic proliferation in response to IL-7 and IL-15, surface expression of tissue-localization (CD103) and -retention (CD69) markers, low levels of inhibitory receptors (PD-1, Tim-3, LAG-3), and a lack of senescence markers (CD57, KLRG1). In contrast, CCR8− skin T cells are heterogeneous and comprise variable numbers of exhausted (PD-1+), senescent (CD57+, KLRG1+), and effector (T-bethi, Eomeshi) T cells. Importantly, conventional and high-throughput analyses of expressed T cell receptor beta-chain (TRB) gene rearrangement sequences showed that the two skin memory T cell compartments distinguished by CCR8 expression are clonotypically distinct, suggesting that they are produced in response to separate antigenic challenges and distinct stimulatory conditions. Moreover, the phenotypic profiles of these populations were stable in vitro and the presence of similar levels of telomere erosion excludes the possibility of a linear differentiation pathway. In conclusion, CCR8 marks skin-specific, long-lived memory T cells. Therefore, we propose that CCR8+ T cells should be targeted in future skin vaccination research.

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