Abstract
The localization of memory T cells to human skin is essential for long-term immune surveillance and the maintenance of barrier integrity. The expression of CCR8 during naive T cell activation is controlled by skin-specific factors derived from epidermal keratinocytes and not by resident dendritic cells. In this study, we show that the CCR8-inducing factors are heat stable and protease resistant and include the vitamin D3 metabolite 1α,25-dihydroxyvitamin D3 and PGE2. The effect of either metabolite alone on CCR8 expression was weak, whereas their combination resulted in robust CCR8 expression. Elevation of intracellular cAMP was essential because PGE2 could be substituted with the adenylyl cyclase agonist forskolin, and CCR8 expression was sensitive to protein kinase A inhibition. For effective induction, exposure of naive T cells to these epidermal factors needed to occur either prior to or during T cell activation even though CCR8 was only detected 4–5 d later in proliferating T cells. The importance of tissue environments in maintaining cellular immune surveillance networks within distinct healthy tissues provides a paradigm shift in adaptive immunity. Epidermal-derived vitamin D3 metabolites and PGs provide an essential cue for the localization of CCR8+ immune surveillance T cells within healthy human skin.
Highlights
We show a mechanism for the control of human CCR8 expression involving the skin-produced metabolites 1,25-dihydroxyvitamin D3 and PG E2
This effect was only observed at high concentrations of PGE2, whereas induction of CCR8 at concentrations of PGE2 produced by steady-state epidermis only occurred in the presence of the active vitamin D metabolite, 1,25(OH)2D3
In the presence of the inflammatory cytokines IL-12 [10] or TNF-a plus IL-6 [30], 1,25(OH)2D3, induces low-level expression of the chemokine receptor CCR10 in T cells, whereas in the presence of basal levels of PGE2, we found that 1,25(OH)2D3 synergistically enhanced expression of CCR8
Summary
Even pulsing naive T cells with ECM (i.e., 18-h culture followed by a washing step) prior to TCR triggering resulted in significant CCR8 induction, indicating that the active factor(s) could “imprint” resting T cells for skin homing (Fig. 1E). Incubating naive T cells with ECM for 30 min resulted in a transient 2.5-fold increase of intracellular cAMP levels over media alone (Fig. 3A), suggesting that cAMPmediated signaling events may be involved in the regulation of CCR8 expression.
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