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.

Expansion of CD8+ T cells lacking Sema4D/CD100 during HIV-1 infection identifies a subset of T cells with decreased functional capacity

“…5,8,9,32 Therefore we hypothesized that the number of CD100 ϩ CD8 ϩ T cells would directly relate to the magnitude of the antigen-specific T-cell responses. To elucidate whether antigenspecific CD8 ϩ T cells in general, or if HIV-1-specific CD8 ϩ T cells in particular, had decreased CD100 expression in HIV-1-infected patients, pentamer staining was performed on PBMCs from seronegative and chronically HIV-1-infected individuals ( Figure 3A-B).…”

“…8 In addition, CD100 appears to be important for differentiation into effector T cells. 5,8,9 The importance of CD8 ϩ T-cell immunity during HIV-1 infection is well established. As HIV-1-specific CD8 ϩ T cells emerge during acute infection, plasma viremia rapidly decreases.…”

“…5,8,9,32,33 We hypothesized that lower levels of CD100 reduce effector functions that render T cells incapable of optimally responding to pathogens. We used subjects at different stages of HIV-1 infection to determine the effect of infection on CD100 expression and to assess the potential role of CD100 for CD8 ϩ T cell responses.…”

Siglec-G represses DAMP-mediated effects on T cells

“…In the in vivo experiments, the BALB/c WT and CD24 -/-BALB/c animals received 850 cGy total body irradiation ( ) were purchased from American Type Culture Collection (ATCC) and introduced during BMT at 2 different doses as described previously (41). To observe GVT responses, we utilized the lower dose of tumor cells (P815, 1 × 10 3 to 5 × 10 3 /mouse) because even at this low dose we already established that the animals cannot reject the tumor cells and that this tumor is uniformly lethal and results in tumor infiltration and engraftment of the liver and spleen with characteristic nodule formation or hind-limb paralysis caused by spinal cord infiltration (41).…”

“…To observe GVT responses, we utilized the lower dose of tumor cells (P815, 1 × 10 3 to 5 × 10 3 /mouse) because even at this low dose we already established that the animals cannot reject the tumor cells and that this tumor is uniformly lethal and results in tumor infiltration and engraftment of the liver and spleen with characteristic nodule formation or hind-limb paralysis caused by spinal cord infiltration (41). We concluded that tumor contributed to death only if the tumor was present at the necropsy.…”