title: Intestinal tolerance is converted to autoimmune enteritis upon PD-1 ligand blockade.
abstract: The B7 family member programmed death-1 ligand (PD-L1) has been shown to play an inhibitory role in the regulation of T cell responses in several organs. However, the role of PD-L1 in regulating tolerance to self-Ags of the small intestine has not been previously addressed. In this study, we investigated the role of PD-L1 in CD8(+) T cell tolerance to an intestinal epithelium-specific Ag using the iFABP-tOVA transgenic mouse model, in which OVA is expressed as a self-Ag throughout the small intestine. Using adoptive transfer of naive OVA-specific CD8(+) T cells, we show that loss of PD-1:PD-L1 signaling, by either Ab-mediated PD-L1 blockade or transfer of PD-1(-/-) T cells, leads to considerable expansion of OVA-specific CD8(+) T cells and their differentiation into effector cells capable of producing proinflammatory cytokines. A fatal CD8(+) T cell-mediated inflammatory response develops rapidly against the small bowel causing destruction of the epithelial barrier, severe blunting of intestinal villi, and recruitment and activation of myeloid cells. This response is highly specific because immune destruction selectively targets the small intestine but not other organs. Collectively, these results indicate that loss of the PD-1:PD-L1 inhibitory pathway breaks CD8(+) T cell tolerance to intestinal self-Ag, thus leading to severe enteric autoimmunity.
authors.affiliation: Division of Medical Sciences, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Erika D
authors.initials: ED
authors.lastname: Reynoso
authors.forename: Kutlu G
authors.initials: KG
authors.lastname: Elpek
authors.forename: Loise
authors.initials: L
authors.lastname: Francisco
authors.forename: Roderick
authors.initials: R
authors.lastname: Bronson
authors.forename: Angélique
authors.initials: A
authors.lastname: Bellemare-Pelletier
authors.forename: Arlene H
authors.initials: AH
authors.lastname: Sharpe
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: Shannon J
authors.initials: SJ
authors.lastname: Turley
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000954:Antigens, Surface / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology*; D018122:B7-1 Antigen / Q000276:immunology* / Q000378:metabolism; D060890:B7-H1 Antigen; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D004751:Enteritis / Q000276:immunology*; D005434:Flow Cytometry; D007108:Immune Tolerance / Q000276:immunology*; D018928:Immunity, Mucosal / Q000276:immunology*; D007422:Intestines / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D010455:Peptides / Q000276:immunology* / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor
chemical_list: D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D001324:Autoantigens; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D008562:Membrane Glycoproteins; C491383:Pdcd1 protein, mouse; D010455:Peptides; D061026:Programmed Cell Death 1 Receptor; D010047:Ovalbumin