A novel role for the semaphorin Sema4D in the induction of allo-responses.
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.
Duran-Struuck
Raimon
R
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Tawara
Isao
I
Lowler
Kathi
K
Clouthier
Shawn G
SG
Weisiger
Elizabeth
E
Rogers
Clare
C
Luker
Gary
G
Kumanogoh
Atsushi
A
Liu
Chen
C
Ferrara
James L M
JL
Reddy
Pavan
P
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
C103150:Sema4d protein, mouse; D039961:Semaphorins