title: B7x in the periphery abrogates pancreas-specific damage mediated by self-reactive CD8 T cells.
abstract: B7x (B7-H4 or B7S1) is the seventh member of the B7 family, and its in vivo function remains largely unknown. Despite new genetic data linking the B7x gene with autoimmune diseases, how exactly it contributes to peripheral tolerance and autoimmunity is unclear. In this study, we showed that B7x protein was not detected on APCs or T cells in both human and mice, which is unique in the B7 family. Because B7x protein is expressed in some peripheral cells such as pancreatic β cells, we used a CD8 T cell-mediated diabetes model (AI4αβ) in which CD8 T cells recognize an endogenous self-Ag, and found that mice lacking B7x developed more severe diabetes than control AI4αβ mice. Conversely, mice overexpressing B7x in the β cells (Rip-B7xAI4αβ) were diabetes free. Furthermore, adoptive transfer of effector AI4αβ CD8 T cells induced diabetes in control mice, but not in Rip-B7xAI4αβ mice. Mechanistic studies revealed that pathogenic effector CD8 T cells were capable of migrating to the pancreas but failed to robustly destroy tissue when encountering local B7x in Rip-B7xAI4αβ mice. Although AI4αβ CD8 T cells in Rip-B7xAI4αβ and AI4αβ mice showed similar cytotoxic function, cell death, and global gene expression profiles, these cells had greater proliferation in AI4αβ mice than in RIP-B7xAI4αβ mice. These results suggest that B7x in nonlymphoid organs prevents peripheral autoimmunity partially through inhibiting proliferation of tissue-specific CD8 T cells, and that local overexpression of B7x on pancreatic β cells is sufficient to abolish CD8 T cell-induced diabetes.
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Jun Sik
authors.initials: JS
authors.lastname: Lee
authors.forename: Lisa
authors.initials: L
authors.lastname: Scandiuzzi
authors.forename: Anjana
authors.initials: A
authors.lastname: Ray
authors.forename: Joyce
authors.initials: J
authors.lastname: Wei
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Hofmeyer
authors.forename: Yael M
authors.initials: YM
authors.lastname: Abadi
authors.forename: P'ng
authors.initials: P
authors.lastname: Loke
authors.forename: Juan
authors.initials: J
authors.lastname: Lin
authors.forename: Jianda
authors.initials: J
authors.lastname: Yuan
authors.forename: David V
authors.initials: DV
authors.lastname: Serreze
authors.forename: James P
authors.initials: JP
authors.lastname: Allison
authors.forename: Xingxing
authors.initials: X
authors.lastname: Zang
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000097:blood*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology* / Q000637:transplantation; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D060467:Disease Resistance; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010179:Pancreas / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1 / Q000096:biosynthesis / Q000097:blood* / Q000235:genetics
chemical_list: D001324:Autoantigens; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1