title: Keratinocyte-associated B7-H1 directly regulates cutaneous effector CD8+ T cell responses.
abstract: Keratinocytes (KCs) may play important roles for maintenance of peripheral tolerance in the upper layers of the skin. Coinhibitory signals mediated via the programmed death (PD)-1 and its ligand B7-H1 (PD-L1/CD274) are crucial for the downregulation of T cell immune responses and for the maintenance of peripheral tolerance. In this study, to investigate the role of KC-expressed B7-H1 in the regulation of T cell immune responses, we generated transgenic (tg) mice overexpressing B7-H1 under the control of keratin 14 (K14) promoter (K14-B7-H1 tg). K14-B7-H1 tg mice displayed impaired contact hypersensitivity (CH) responses to primary and secondary hapten challenges. The K14-B7-H1 tg mice did not exhibit substantial impairment of cutaneous dendritic cell migration after sensitization and of hapten-specific proliferation and IFN-gamma production of CD4(+) and CD8(+) T cells in the draining lymph nodes, suggesting that overexpression of B7-H1 on KCs did not affect the induction phase of the CH response. The systemic or s.c. injection of hapten-sensitized T cells into the K14-B7-H1 tg mice did not efficiently induce the CH response. IFN-gamma expression and apoptosis of KCs in the challenged ears were impaired in K14-B7-H1 tg mice. IFN-gamma production by presensitized CD8(+) T cells stimulated with hapten-pulsed KCs was markedly impaired for the KCs obtained from the K14-B7-H1 tg mice but was restored by the addition of an anti-B7-H1 mAb. These results suggest that KC-associated B7-H1 directly downregulates the effector function of CD8(+) T cells by associating with PD-1 at local inflammatory sites and that it plays a role in peripheral T cell tolerance against exogenous Ags.
authors.affiliation: Department of Molecular Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Patcharee
authors.initials: P
authors.lastname: Ritprajak
authors.forename: Masaaki
authors.initials: M
authors.lastname: Hashiguchi
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Tsushima
authors.forename: Narumon
authors.initials: N
authors.lastname: Chalermsarp
authors.forename: Miyuki
authors.initials: M
authors.lastname: Azuma
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D018122:B7-1 Antigen / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D060890:B7-H1 Antigen; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D003877:Dermatitis, Contact / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology; D019169:Jurkat Cells; D053547:Keratin-14 / Q000235:genetics; D015603:Keratinocytes / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010455:Peptides / Q000235:genetics / Q000502:physiology*; D061026:Programmed Cell Death 1 Receptor; D011401:Promoter Regions, Genetic / Q000276:immunology; D012867:Skin / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology
chemical_list: D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D018836:Inflammation Mediators; D053547:Keratin-14; D008562:Membrane Glycoproteins; C105992:PDCD1 protein, human; D010455:Peptides; D061026:Programmed Cell Death 1 Receptor