Indirect recruitment of a CD40 signaling pathway in dendritic cells by B7-DC cross-linking antibody modulates T cell functions.
The human IgM B7-DC XAb protects mice from tumors in both therapeutic and prophylactic settings. Its mechanism of action is mediated by its binding to B7-DC/PD-L2 molecules on the surface of dendritic cells (DCs) to induce a multimolecular cap and subsequent activation of signaling cascades that determine a unique combination of DC phenotypes. One such phenotype, the B7-DC XAb-induced antigen accumulation in mTLR-matured DCs, has been linked to signaling through TREM-2, but the signals required for other DC phenotypes critical for the therapeutic effects in animal models remain unclear. Here, FRET and co-immunoprecipitation studies show that CD40 is recruited to the multi-molecular complex by B7-DC XAb. Signals emanating from CD40 are important, as CD40(-/-) DCs treated with B7-DC XAb (DC(XAb)) activated DAP12, but failed to activate NFkappaB, and were not protected from cell death upon cytokine withdrawal or treatment with Vitamin D(3). CD40(-/-) DC(XAb) also failed to secrete IL-6 and were unable to support the conversion of T regulatory cells into IL-17+ effector T cells in vitro. Importantly, the expression of CD40 was required for the overall ability of B7-DC XAb to induce anti-tumor CTL, to provide protection from a number of tumor types, and for DC(XAb) to be effective anti-tumor vaccines in vivo. These results indicate that B7-DC XAb modulation of DC phenotypes is through its ability to indirectly recruit common signaling molecules and elements of their endogenous signaling pathways through targeted binding to a cell-specific surface determinant.
Radhakrishnan
Suresh
S
Department of Immunology, College of Medicine, Mayo Clinic, Rochester, MN, USA.
Cabrera
Rosalyn
R
Bruns
Kristina M
KM
Van Keulen
Virginia P
VP
Hansen
Michael J
MJ
Felts
Sara J
SJ
Pease
Larry R
LR
D000818:Animals; D000910:Antibodies, Heterophile; D051940:B7-2 Antigen / Q000378:metabolism*; D019013:CD40 Antigens / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002450:Cell Communication; D002470:Cell Survival; D003432:Cross-Linking Reagents; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D006801:Humans; D007152:Immunologic Capping; D066298:In Vitro Techniques; D020381:Interleukin-17 / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D010641:Phenotype; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
D000910:Antibodies, Heterophile; D051940:B7-2 Antigen; D019013:CD40 Antigens; D003432:Cross-Linking Reagents; D020381:Interleukin-17; D015850:Interleukin-6; D016328:NF-kappa B