title: IL-10 conditioning of human skin affects the distribution of migratory dendritic cell subsets and functional T cell differentiation.
abstract: In cancer patients pervasive systemic suppression of Dendritic Cell (DC) differentiation and maturation can hinder vaccination efficacy. In this study we have extensively characterized migratory DC subsets from human skin and studied how their migration and T cell-stimulatory abilities were affected by conditioning of the dermal microenvironment through cancer-related suppressive cytokines. To assess effects in the context of a complex tissue structure, we made use of a near-physiological skin explant model. By 4-color flow cytometry, we identified migrated Langerhans Cells (LC) and five dermis-derived DC populations in differential states of maturation. From a panel of known tumor-associated suppressive cytokines, IL-10 showed a unique ability to induce predominant migration of an immature CD14(+)CD141(+)DC-SIGN(+) DC subset with low levels of co-stimulatory molecules, up-regulated expression of the co-inhibitory molecule PD-L1 and the M2-associated macrophage marker CD163. A similarly immature subset composition was observed for DC migrating from explants taken from skin overlying breast tumors. Whereas predominant migration of mature CD1a(+) subsets was associated with release of IL-12p70, efficient Th cell expansion with a Th1 profile, and expansion of functional MART-1-specific CD8(+) T cells, migration of immature CD14(+) DDC was accompanied by increased release of IL-10, poor expansion of CD4(+) and CD8(+) T cells, and skewing of Th responses to favor coordinated FoxP3 and IL-10 expression and regulatory T cell differentiation and outgrowth. Thus, high levels of IL-10 impact the composition of skin-emigrated DC subsets and appear to favor migration of M2-like immature DC with functional qualities conducive to T cell tolerance.
authors.affiliation: Department of Medical Oncology, VU University medical center, Amsterdam, The Netherlands.
authors.forename: Jelle J
authors.initials: JJ
authors.lastname: Lindenberg
authors.forename: Dinja
authors.initials: D
authors.lastname: Oosterhoff
authors.forename: Claudia C
authors.initials: CC
authors.lastname: Sombroek
authors.forename: Sinéad M
authors.initials: SM
authors.lastname: Lougheed
authors.forename: Erik
authors.initials: E
authors.lastname: Hooijberg
authors.forename: Anita G M
authors.initials: AG
authors.lastname: Stam
authors.forename: Saskia J A M
authors.initials: SJ
authors.lastname: Santegoets
authors.forename: Henk J
authors.initials: HJ
authors.lastname: Tijssen
authors.forename: Jan
authors.initials: J
authors.lastname: Buter
authors.forename: Herbert M
authors.initials: HM
authors.lastname: Pinedo
authors.forename: Alfons J M
authors.initials: AJ
authors.lastname: van den Eertwegh
authors.forename: Rik J
authors.initials: RJ
authors.lastname: Scheper
authors.forename: Hans J P M
authors.initials: HJ
authors.lastname: Koenen
authors.forename: Rieneke
authors.initials: R
authors.lastname: van de Ven
authors.forename: Tanja D
authors.initials: TD
authors.lastname: de Gruijl
mesh_terms: D000704:Analysis of Variance; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology*; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology*; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D016753:Interleukin-10 / Q000494:pharmacology*; D007801:Langerhans Cells / Q000276:immunology*; D060888:Real-Time Polymerase Chain Reaction; D011956:Receptors, Cell Surface / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000166:cytology / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology; D000098902:CD163 Antigen
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000098902:CD163 Antigen; D011956:Receptors, Cell Surface; D016753:Interleukin-10