title: A novel role for the semaphorin Sema4D in the induction of allo-responses.
abstract: Sema4D (CD100), a member of the neuro-semaphorin family of proteins, has recently been shown to play a role in modulating certain immune responses. We tested the requirement of Sema4D expression on T cells in the induction of T cell allo-immune responses. Sema4D-/- T cells showed reduced expansion in vitro upon stimulation with allo-geneic antigen presenting cells (APCs) when compared to wild-type (wt) T cells. Similar in vitro results were observed using anti-Sema4D mAbs. Further studies demonstrated that the reduced proliferation was not due to intrinsic T cell defects, and that the cytotoxic functions were preserved. After allo-geneic bone marrow transplant (BMT), recipients of Sema4D-/- T cells showed reduced mortality and graft-versus-host disease (GVHD) target organ damage. Allo-geneic dendritic cells (DCs) cocultured with Sema4D-/- responder T cells secreted less TNF-alpha and IL-12p70 compared to wt T cells. Similar reduction of DC function was observed with anti-Sema4D mAbs. Given the preservation of CTL function we evaluated graft-versus-leukemia (GVL) responses. When BALB/c recipient mice were challenged with the P815 murine mastocytoma cell line (H2(d)) the recipients of allo-geneic Sema4D-/- B6 T cells showed a significant improvement in tumor free survival when compared to syngeneic recipients, thus demonstrating preservation of GVL, albeit of a lesser magnitude than allo-geneic wt T cells. In summary, Sema4D plays a significant role in mediating in vitro and in vivo allo-geneic responses by modulating T cell-APC interactions.
authors.affiliation: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Raimon
authors.initials: R
authors.lastname: Duran-Struuck
authors.forename: Isao
authors.initials: I
authors.lastname: Tawara
authors.forename: Kathi
authors.initials: K
authors.lastname: Lowler
authors.forename: Shawn G
authors.initials: SG
authors.lastname: Clouthier
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Weisiger
authors.forename: Clare
authors.initials: C
authors.lastname: Rogers
authors.forename: Gary
authors.initials: G
authors.lastname: Luker
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kumanogoh
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.forename: James L M
authors.initials: JL
authors.lastname: Ferrara
authors.forename: Pavan
authors.initials: P
authors.lastname: Reddy
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D006086:Graft vs Host Disease / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D039961:Semaphorins / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014184:Transplantation, Homologous / Q000276:immunology
chemical_list: C103150:Sema4d protein, mouse; D039961:Semaphorins