title: PD-1 ligands expressed on myeloid-derived APC in the CNS regulate T-cell responses in EAE.
abstract: Disease progression in experimental autoimmune encephalomyelitis (EAE) is regulated by programmed death receptor 1 (PD-1) and its ligands, B7-H1 (programmed death ligand 1 (PD-L1)) and B7-DC (PD-L2). B7-H1 and B7-DC have negative regulatory effects upon binding PD-1 on activated T cells and B7-H1 deficiency increases severity of both diabetes and EAE. However, the role of PD-L expression on different APC in the CNS in regulating local T-cell function during relapsing EAE has not been examined. Our data show that the majority of CNS CD4+ T cells isolated during acute EAE are PD-1+, and T cells specific for relapse-associated epitopes express PD-1 upon antigen stimulation in the CNS. B7-H1 and B7-DC are differentially expressed on discrete APC populations in the inflamed CNS. B7-H1 and PD-1 have mainly inhibitory functions on CNS T cells. B7-H1 negatively regulates the stimulation of activated PD-1+ T(H) cells, in co-cultures with microglia and different CNS-infiltrating APC presenting endogenously processed peptides. The preponderance of IFN-gamma+ versus IL-17+ T cells in the CNS of B7-H1(-/-) mice suggests that B7-H1 more selectively suppresses T(H)-1 than T(H)-17 responses in vivo. In contrast, blockade of B7-DC has less pronounced regulatory effects. Overall, the results demonstrate that B7-H1 expressed by CNS myeloid APC negatively regulates T-cell activation during acute relapsing EAE.
authors.affiliation: Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Bettina
authors.initials: B
authors.lastname: Schreiner
authors.forename: Samantha L
authors.initials: SL
authors.lastname: Bailey
authors.forename: Tahiro
authors.initials: T
authors.lastname: Shin
authors.forename: Lieping
authors.initials: L
authors.lastname: Chen
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Miller
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000378:metabolism; D000943:Antigens, Differentiation / Q000276:immunology* / Q000378:metabolism; D018122:B7-1 Antigen / Q000276:immunology* / Q000378:metabolism; D060890:B7-H1 Antigen; D002490:Central Nervous System / Q000276:immunology* / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D005260:Female; D055785:Gene Knockdown Techniques; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000276:immunology* / Q000378:metabolism; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism
chemical_list: D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D020381:Interleukin-17; D008562:Membrane Glycoproteins; C491383:Pdcd1 protein, mouse; C556978:Pdcd1lg2 protein, mouse; D010455:Peptides; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D007371:Interferon-gamma