title: Ikaros-Notch axis in host hematopoietic cells regulates experimental graft-versus-host disease.
abstract: Host hematopoietically derived APCs play a vital role in the initiation of GVH responses. However, the APC autonomous molecular mechanisms that are critical for the induction of GVHD are not known. We report here that the Ikaros-Notch axis in host hematopoietically derived APCs regulates the severity of acute GVHD across multiple clinically relevant murine models of experimental bone marrow transplantation. In the present study, Ikaros deficiency (Ik(-/-)) limited to host hematopoietically derived APCs enhanced donor T-cell expansion and intensified acute GVHD, as determined by survival and other GVHD-specific parameters. The Ik(-/-) conventional CD8(+) and CD8(-)CD11c(+) dendritic cells (DCs), the most potent APCs, showed no increase in the expression of activation markers or in response to TLR stimulation compared with wild-type controls. However, Ik(-/-) DCs demonstrated an enhanced stimulation of allogeneic T cells. Deficiency of Ikaros in the conventional CD8(+) and CD8(-)CD11c(+) DCs was associated with an increase in Notch signaling, the blockade of which mitigated the enhanced in vitro and in vivo allostimulatory capacity. Therefore, the Ikaros-Notch axis is a novel pathway that modulates DC biology in general, and targeting this pathway in host hematopoietically derived APCs may reduce GVHD.
authors.affiliation: Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Toubai
authors.forename: Yaping
authors.initials: Y
authors.lastname: Sun
authors.forename: Isao
authors.initials: I
authors.lastname: Tawara
authors.forename: Ann
authors.initials: A
authors.lastname: Friedman
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.forename: Rebecca
authors.initials: R
authors.lastname: Evers
authors.forename: Evelyn
authors.initials: E
authors.lastname: Nieves
authors.forename: Chelsea
authors.initials: C
authors.lastname: Malter
authors.forename: Peter
authors.initials: P
authors.lastname: Chockley
authors.forename: Ivan
authors.initials: I
authors.lastname: Maillard
authors.forename: Susan
authors.initials: S
authors.lastname: Winandy
authors.forename: Pavan
authors.initials: P
authors.lastname: Reddy
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D006410:Hematopoiesis / Q000276:immunology; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016130:Immunophenotyping; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D051881:Receptor, Notch1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*
chemical_list: C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; C497238:Zfpn1a1 protein, mouse; D051740:Ikaros Transcription Factor