title: Skin Metabolites Define a New Paradigm in the Localization of Skin Tropic Memory T Cells.
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.
authors.affiliation: Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, Wales, United Kingdom; and.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: McCully
authors.affiliation: Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, Wales, United Kingdom; and.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Collins
authors.affiliation: Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, Wales, United Kingdom; and.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Hughes
authors.affiliation: Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, Wales, United Kingdom; and.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Thomas
authors.affiliation: Department of Laboratory Medicine, Leuven University Hospital, 3000 Leuven, Belgium.
authors.forename: Jaak
authors.initials: J
authors.lastname: Billen
authors.affiliation: Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, Wales, United Kingdom; and.
authors.forename: Valerie B
authors.initials: VB
authors.lastname: O'Donnell
authors.affiliation: Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, Wales, United Kingdom; and moserb@cardiff.ac.uk.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Moser
mesh_terms: D056704:Adaptive Immunity; D000262:Adenylyl Cyclases / Q000235:genetics / Q000276:immunology; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D002117:Calcitriol / Q000378:metabolism* / Q000494:pharmacology; D000242:Cyclic AMP / Q000276:immunology / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D015232:Dinoprostone / Q000378:metabolism* / Q000494:pharmacology; D000078404:Epidermal Cells; D004817:Epidermis / Q000187:drug effects / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation; D006358:Hot Temperature; D006801:Humans; D007157:Immunologic Surveillance; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D061251:Primary Cell Culture; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D055550:Protein Stability; D054401:Receptors, CCR8 / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction
chemical_list: C103330:CCR8 protein, human; D047428:Protein Kinase Inhibitors; D054401:Receptors, CCR8; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases; D002117:Calcitriol; D015232:Dinoprostone