title: Jagged2-signaling promotes IL-6-dependent transplant rejection.
abstract: The Notch pathway is an important intercellular signaling pathway that plays a major role in controlling cell fate. Accumulating evidence indicates that Notch and its ligands present on antigen-presenting cells might be important mediators of T helper cell differentiation. In this study, we investigated the role of Jagged2 in murine cardiac transplantation by using a signaling Jagged2 mAb (Jag2) that activates recombinant signal-binding protein-Jκ. While administration of Jag2 mAb had little effect on graft survival in the fully allogeneic mismatched model BALB/c→B6, it hastened rejection in CD28-deficient recipients. Similarly, Jag2 precipitated rejection in the bm12→B6 model. In this MHC class II-mismatched model, allografts spontaneously survive for >56 days due to the emergence of Treg cells that inhibit the expansion of alloreactive T cells. The accelerated rejection was associated with upregulation of Th2 cytokines and proinflammatory cytokine IL-6, despite expansion of Treg cells. Incubation of Treg cells with recombinant IL-6 abrogated their inhibitory effects in vitro. Furthermore, neutralization of IL-6 in vivo protected Jag2-treated recipients from rejection and Jagged2 signaling was unable to further accelerate rejection in the absence of Treg cells. Our findings therefore suggest that Jagged2 signaling can affect graft acceptance by upregulation of IL-6 and consequent resistance to Treg-cell suppression.
authors.affiliation: Transplantation Research Center, Renal Division, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. lriella@rics.bwh.harvard.edu
authors.forename: Leonardo V
authors.initials: LV
authors.lastname: Riella
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Susanne
authors.initials: S
authors.lastname: Chock
authors.forename: Kassem
authors.initials: K
authors.lastname: Safa
authors.forename: Ciara N
authors.initials: CN
authors.lastname: Magee
authors.forename: Vijay
authors.initials: V
authors.lastname: Vanguri
authors.forename: Wassim
authors.initials: W
authors.lastname: Elyaman
authors.forename: Youmna
authors.initials: Y
authors.lastname: Lahoud
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Reza
authors.initials: R
authors.lastname: Abdi
authors.forename: Nader
authors.initials: N
authors.lastname: Najafian
authors.forename: José O
authors.initials: JO
authors.lastname: Medina-Pestana
authors.forename: Anil
authors.initials: A
authors.lastname: Chandraker
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D018106:CD28 Antigens / Q000235:genetics; D002478:Cells, Cultured; D006084:Graft Rejection / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D006649:Histocompatibility Antigens / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology*; D000072101:Jagged-2 Protein; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D018418:Th2 Cells / Q000187:drug effects* / Q000276:immunology
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D006649:Histocompatibility Antigens; D015850:Interleukin-6; C490503:Jag2 protein, mouse; D000072101:Jagged-2 Protein; D008565:Membrane Proteins