title: B7H1/CD80 interaction augments PD-1-dependent T cell apoptosis and ameliorates graft-versus-host disease.
abstract: Interactions of B7H1 (programmed death ligand 1 [PD-L1]) with its two ligands, PD-1 and CD80, on T cells play a pivotal role in controlling T cell activation, proliferation, anergy, and apoptosis. However, the interactions between the two pathways remain unknown. Using an alloimmune response model of graft-versus-host disease (GVHD), we report in this study that: 1) Comparison of proliferation and apoptosis of wild-type (WT) and PD-1(-/-)CD4(+) conventional T (Tcon) cells in WT and B7H1(-/-) recipients revealed that B7H1/CD80 interaction per se augments T cell proliferation, and this interaction augments T cell apoptosis mediated by B7H1/PD-1 interaction. This observation was recapitulated in an in vitro MLR assay. 2) Specific blockade of the B7H1/CD80 axis by anti-B7H1 mAb reduces WT-alloreactive Tcon cell proliferation, IL-2 production, expression of PD-1, and apoptosis, resulting in worsening GVHD. In contrast, specific blockade of B7H1/CD80 interaction reduces donor PD-1(-/-) Tcon cell proliferation without an impact on apoptosis, resulting in ameliorating GVHD. 3) B7H1 fused to an Ig Fc domain (B7H1-Ig), when produced in vivo by hydrodynamic injection of B7H1-Ig plasmid, ameliorates GVHD by augmenting proliferation and apoptosis of WT- alloreactive Tcon cells. Conversely, B7H1-Ig treatment has no impact on apoptosis but augments PD-1(-/-) T cell proliferation and worsens GVHD. These results indicate that B7H1/CD80 interaction augments Tcon cell proliferation, IL-2 production, and expression of PD-1, which leads to increased apoptosis mediated by the B7H1/PD-1 pathway. Additionally, by engaging both PD-1 and CD80, B7H1-Ig can be a powerful therapeutic reagent for downregulating the T cell immune response.
authors.affiliation: Department of Diabetes Research, Beckman Research Institute, City of Hope, Duarte, CA 91010; Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope, Duarte, CA 91010;
authors.forename: Ruishu
authors.initials: R
authors.lastname: Deng
authors.affiliation: Department of Diabetes Research, Beckman Research Institute, City of Hope, Duarte, CA 91010; Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope, Duarte, CA 91010; Irell and Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA 91010;
authors.forename: Kaniel
authors.initials: K
authors.lastname: Cassady
authors.affiliation: Department of Diabetes Research, Beckman Research Institute, City of Hope, Duarte, CA 91010; Department of Hematology, Fujian Institute of Hematology, Fujian Medical University Union Hospital, Fuzhou 350001, China;
authors.forename: Xiaofan
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520; and.
authors.forename: Sheng
authors.initials: S
authors.lastname: Yao
authors.affiliation: Department of Diabetes Research, Beckman Research Institute, City of Hope, Duarte, CA 91010; Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope, Duarte, CA 91010;
authors.forename: Mingfeng
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Diabetes Research, Beckman Research Institute, City of Hope, Duarte, CA 91010; Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope, Duarte, CA 91010; Irell and Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA 91010;
authors.forename: Jeremy
authors.initials: J
authors.lastname: Racine
authors.affiliation: Eugene and Ruth Roberts Summer Student Academy of City of Hope, Duarte, CA 91010.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Lin
authors.affiliation: Department of Hematology, Fujian Institute of Hematology, Fujian Medical University Union Hospital, Fuzhou 350001, China;
authors.forename: Lieping
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Diabetes Research, Beckman Research Institute, City of Hope, Duarte, CA 91010; Department of Hematology and Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope, Duarte, CA 91010; Irell and Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA 91010; dzeng@coh.org.
authors.forename: Defu
authors.identifier: http://orcid.org/0000-0001-9585-1411
authors.initials: D
authors.lastname: Zeng
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology*; D060890:B7-H1 Antigen / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D049109:Cell Proliferation / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology
chemical_list: D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D007376:Interleukin-2; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011993:Recombinant Fusion Proteins