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Updated: Aug 8, 2026
Generation of Human CD40-activated B cells
Published on: October 17, 2009
Triggering of murine NK cells by CD40 and CD86 (B7-2)
A Martín-Fontecha1, E Assarsson, E Carbone
1Microbiology and Tumor Biology Center, Karolinska Institutet, Stockholm, Sweden. Alfonso.Martin-Fontecha@mtc.ki.se
Insights
Murine CD40 and CD86 (B7-2) costimulatory molecules activate natural killer (NK) cell cytotoxicity against tumor cells. These molecules also mediate NK cell-dependent tumor cell elimination in vivo, independent of CD28 and CD40 ligand.
Area of Science:
- Immunology
- Cellular Biology
- Cancer Research
Background:
- Natural killer (NK) cell cytotoxicity is crucial for immune surveillance and is regulated by activating and inhibitory signals.
- MHC class I interactions typically inhibit NK cell activity, but other molecules can trigger cytotoxicity.
- Previous work identified CD80 (B7-1) and CD40 as activators of NK cell-mediated cytotoxicity.
Purpose of the Study:
- To investigate the role of murine CD40 and CD86 (B7-2) in triggering NK cell-mediated cytotoxicity against tumor cells.
- To determine if CD40 and B7-2 mediate NK cell-dependent tumor cell elimination in vivo.
- To explore the specific NK cell receptors involved in CD40 and B7-2 mediated activation.
Main Methods:
- Transfection of tumor cell lines with murine CD40 and CD86 (B7-2).
- In vitro cytotoxicity assays using NK cells and transfected tumor cells.
- In vivo tumor cell elimination studies in wild-type and knockout mice (CD40L-/-, CD28-/-).
- Blocking experiments using anti-CD40 F(ab')2 fragments and CTLA-4-Ig.
Main Results:
- Murine CD40 and CD86 (B7-2) expressed on tumor cells triggered NK cell-mediated cytotoxicity in vitro.
- Preincubation with anti-CD40 F(ab')2 or CTLA-4-Ig blocked the triggering effect of CD40 and B7-2, respectively.
- CD40- and B7-2-expressing tumor cells were rapidly eliminated in vivo in an NK cell-dependent manner.
- Tumor cell elimination occurred even in CD40L-/- and CD28-/- mice, suggesting alternative receptor interactions.
Conclusions:
- Costimulatory molecules CD40 and B7-2 can activate NK cell responses in vitro and in vivo.
- These molecules mediate NK cell-dependent elimination of tumor cells.
- NK cell activation by CD40 and B7-2 involves receptors other than CD40L and CD28.
Abstract:
NK cell-mediated cytotoxicity is regulated by both triggering and inhibitory signals. The interaction between MHC class I molecules expressed on target cells and specific MHC class I-binding receptors expressed by NK cells generally leads to inhibition of lysis. We have shown recently that CD80 (B7-1) in mice and CD40 in humans trigger NK cell-mediated cytotoxicity in vitro. In the present study, we show that murine CD40 and CD86 (B7-2) trigger murine NK cell-mediated cytotoxicity in vitro when expressed on tumor cells. Preincubation of the transfected cell lines with anti-CD40 F(ab')2 fragments or cytolytic T lymphocyte-associated Ag-4-Ig (CTLA-4-Ig) before the cytotoxic assay abolished the triggering effect. Furthermore, radiolabeled CD40- and B7-2-expressing cells were rapidly eliminated in vivo in an NK cell-dependent manner. NK cells from CD40 ligand (CD40L)-/- or CD28-/- mice were triggered by tumor cells transfected with CD40 and B7-2, respectively, and these transfectants were rapidly eliminated in vivo when inoculated into CD40L-/- and CD28-/- mice. This suggests that the CD40 and B7-2 molecules can interact with receptors on NK cells other than CD40L and CD28, respectively, and that these may account for some of the reactivities observed in the present study. Collectively, these data demonstrate that 1) costimulatory molecules, other than B7-1, can modulate NK cell responses in vitro, 2) they can also affect NK cell-dependent responses in vivo, and 3) parts of these reactions are independent of CD28 and CD40L.
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