Indirect recruitment of a CD40 signaling pathway in dendritic cells by B7-DC cross-linking antibody modulates T cell functions

Suresh Radhakrishnan, Rosalyn Cabrera, Kristina M. Bruns, Virginia P. Van Keulen, Michael J. Hansen, Sara J. Felts, Larry R Pease

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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 NFκB, 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.

Original languageEnglish (US)
Article numbere5373
JournalPLoS One
Volume4
Issue number4
DOIs
StatePublished - Apr 28 2009

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T-cells
dendritic cells
crosslinking
Dendritic Cells
T-lymphocytes
T-Lymphocytes
antibodies
Antibodies
Phenotype
phenotype
Tumors
neoplasms
Neoplasms
therapeutics
Cancer Vaccines
Molecules
Interleukin-17
cholecalciferol
Cholecalciferol
Therapeutic Uses

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Indirect recruitment of a CD40 signaling pathway in dendritic cells by B7-DC cross-linking antibody modulates T cell functions. / Radhakrishnan, Suresh; Cabrera, Rosalyn; Bruns, Kristina M.; Van Keulen, Virginia P.; Hansen, Michael J.; Felts, Sara J.; Pease, Larry R.

In: PLoS One, Vol. 4, No. 4, e5373, 28.04.2009.

Research output: Contribution to journalArticle

Radhakrishnan, Suresh ; Cabrera, Rosalyn ; Bruns, Kristina M. ; Van Keulen, Virginia P. ; Hansen, Michael J. ; Felts, Sara J. ; Pease, Larry R. / Indirect recruitment of a CD40 signaling pathway in dendritic cells by B7-DC cross-linking antibody modulates T cell functions. In: PLoS One. 2009 ; Vol. 4, No. 4.
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