title: Programmed cell death 1 (PD-1) regulates the effector function of CD8 T cells via PD-L1 expressed on target keratinocytes.
abstract: Programmed cell death 1 (PD-1) is an inhibitory molecule expressed by activated T cells. Its ligands (PD-L1 and -L2; PD-Ls) are expressed not only by a variety of leukocytes but also by stromal cells. To assess the role of PD-1 in CD8 T cell-mediated diseases, we used PD-1-knockout (KO) OVA-specific T cell-receptor transgenic (Tg) CD8 T cells (OT-I cells) in a murine model of mucocutaneous graft-versus-host disease (GVHD). We found that mice expressing OVA on epidermal keratinocytes (K14-mOVA mice) developed markedly enhanced GVHD-like disease after transfer of PD-1-KO OT-I cells as compared to those mice transferred with wild-type OT-I cells. In addition, K14-mOVA × OT-I double Tg (DTg) mice do not develop GVHD-like disease after adoptive transfer of OT-I cells, while transfer of PD-1-KO OT-I cells caused GVHD-like disease in a Fas/Fas-L independent manner. These results suggest that PD-1/PD-Ls-interactions have stronger inhibitory effects on pathogenic CD8 T cells than does Fas/Fas-L-interactions. Keratinocytes from K14-mOVA mice with GVHD-like skin lesions express PD-L1, while those from mice without the disease do not. These findings reflect the fact that primary keratinocytes express PD-L1 when stimulated by interferon-γ in vitro. When co-cultured with K14-mOVA keratinocytes for 2 days, PD-1-KO OT-I cells exhibited enhanced proliferation and activation compared to wild-type OT-I cells. In addition, knockdown of 50% PD-L1 expression on the keratinocytes with transfection of PD-L1-siRNA enhanced OT-I cell proliferation. In aggregate, our data strongly suggest that PD-L1, expressed on activated target keratinocytes presenting autoantigens, regulates autoaggressive CD8 T cells, and inhibits the development of mucocutaneous autoimmune diseases.
authors.affiliation: Dermatology Branch, National Cancer Institute, National Institutes of Health, Bldg 10, 12N250, 10 Center Dr, Bethesda, MD 20892, USA. Electronic address: naoko.okiyama@nih.gov.
authors.forename: Naoko
authors.initials: N
authors.lastname: Okiyama
authors.affiliation: Dermatology Branch, National Cancer Institute, National Institutes of Health, Bldg 10, 12N250, 10 Center Dr, Bethesda, MD 20892, USA. Electronic address: katzs@od.niams.nih.gov.
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Katz
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D060890:B7-H1 Antigen / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D049109:Cell Proliferation; D005786:Gene Expression Regulation / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology; D015603:Keratinocytes / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000276:immunology*; D012871:Skin Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology
chemical_list: D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor
keywords: CD8 T cell; Fas; Graft-versus-host-disease; Keratinocyte; Programmed cell death 1; Programmed cell death ligand 1