title: Resting but not CpG stimulated keratinocytes suppress autologous T-helper cell proliferation--importance of PGE2 and T regulatory function.
abstract: In the last decade, keratinocytes have increasingly been recognized to actively participate in the skin immune response. However, their influence on infiltrating lymphocytes - abundantly found in e.g. atopic and psoriatic inflammation - is still controversial. In this study, we aimed to investigate the influence of keratinocytes on T-cell proliferation by use of an autologous co-culture model. Because the skin has an important function with regard to detecting invading pathogens, we also investigated the influence of pathogen-associated molecular pattern on keratinocyte - T-cell interaction. We observed a clear inhibition of T-cell proliferation by co-cultured keratinocytes. This effect was found to be mediated by PGE2, as T-cell proliferation was recovered in the presence of the PGE2 inhibitor indometacin. Furthermore, presence of keratinocytes led to enhanced expression of the T regulatory cell-specific transcription factor Foxp3 in the CD4+CD25+ T-cell population which also showed regulatory function. Interestingly, the presence of the TLR9 ligand CpG was able to prevent the inhibition of T-cell proliferation. This was paralleled by a reduced PGE2 production by keratinocytes and a down-regulated T regulatory cell function. Our results indicate that the inhibitory capacity of keratinocytes in the skin is strongly influenced by the surrounding micromillieu.
authors.affiliation: Department of Dermatology and Allergy, Division of Immunodermatology and Allergy Research, Hannover Medical School, Hannover, Germany. Kopfnagel.Verena@mh-hannover.de
authors.forename: Verena
authors.initials: V
authors.lastname: Kopfnagel
authors.forename: Thomas
authors.initials: T
authors.lastname: Werfel
authors.forename: Miriam
authors.initials: M
authors.lastname: Wittmann
mesh_terms: D000527:Alprostadil / Q000031:analogs & derivatives / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D018920:Coculture Techniques; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D007213:Indomethacin / Q000494:pharmacology; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000378:metabolism; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000819:agonists; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000819:agonists; D051193:Toll-Like Receptors / Q000819:agonists; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C408982:CPG-oligonucleotide; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508609:IL10 protein, human; D009838:Oligodeoxyribonucleotides; C545644:PTGER2 protein, human; D058307:Receptors, Prostaglandin E, EP2 Subtype; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D007371:Interferon-gamma; D000527:Alprostadil; C048491:butaprost; D015232:Dinoprostone; D007213:Indomethacin