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Isolation Protocol of Mouse Monocyte-derived Dendritic Cells and Their Subsequent In Vitro Activation with Tumor Immune Complexes
Published on: May 31, 2018
T cells which do not express membrane tumor necrosis factor-alpha activate macrophage effector function by cell
1Department of Biochemistry, College of Medicine, East Tennessee State University, Johnson City 37614.
Abstract:
Previous studies have suggested that T cell contact-dependent signaling of macrophages (Mphi) is mediated by membrane tumor necrosis factor-alpha (memTNF-alpha), based on the observation that anti-TNF-alpha could inhibit T cell-mediated Mphi activation. The current report confirms that anti-TNF-alpha does inhibit activation of interferon-gamma (IFN-gamma)-primed Mphi by paraformaldehyde-fixed activated T cells. However, the involvement of membrane molecules other than memTNF-alpha in the contact-dependent signaling is suggested by two lines of evidence. First, the TH2 clone, AK8, displayed neither secreted TNF-alpha/beta nor memTNF-alpha/beta detectable by bioassay or immunofluorescence. Nonetheless, AK8 cells were equally effective, on a per cell basis, in contact-dependent signaling of M phi activation as TH2 and TH1 cells which do express memTNF-alpha. Second, the expression of memTNF-alpha by the TH2 clone, D10.G4, is maximal 24 h after activation, whereas the ability of this clone to activate Mphi is maximal at 6-8 of activation and declines thereafter. Since TNF-alpha is known to play a critical role in activation of Mphi effector function, it was hypothesized that T cell membrane components other than memTNF-alpha might signal Mphi production of TNF-alpha, thus allowing autocrine TNF-alpha stimulation of Mphi effector function. In support of this, it is demonstrated that paraformaldehyde-fixed activated TH2 cells can induce de novo production and release of TNF-alpha by Mphi. This effect was not an artifactual result of paraformaldehyde fixation since paraformaldehyde-fixed resting T cells did not induce TNF-alpha gene expression. Previous studies have demonstrated a role for autocrine TNF-alpha stimulation in LPS induction of effector function in recombinant IFN-gamma-primed Mphi. The current study confirms that TNF-alpha plays a critical role in T cell contact-dependent signaling of Mphi but indicates that memTNF on the T cells may not be a sine qua non factor for contact-dependent signaling. The data suggest that other T cell membrane molecules contribute to activation of Mphi effector function by stimulation of M phi TNF-alpha production.
Insights
T cell contact-dependent signaling activates macrophages (Mphi), but membrane tumor necrosis factor-alpha (memTNF-alpha) isn't the sole mediator. Other T cell membrane molecules stimulate Mphi to produce TNF-alpha for autocrine activation.
Area of Science:
- Immunology
- Cellular Signaling
- Macrophage Biology
Background:
- Previous research implicated membrane tumor necrosis factor-alpha (memTNF-alpha) in T cell-mediated macrophage (Mphi) activation.
- Anti-TNF-alpha antibodies inhibit T cell-induced Mphi activation, supporting the role of TNF-alpha.
- The precise T cell molecules involved in contact-dependent Mphi signaling require further elucidation.
Purpose of the Study:
- To investigate the role of memTNF-alpha in T cell-dependent Mphi activation.
- To identify alternative T cell membrane molecules involved in Mphi activation signaling.
- To explore the mechanism of Mphi activation, including autocrine TNF-alpha production.
Main Methods:
- Used anti-TNF-alpha to assess Mphi activation by T cells.
- Utilized T cell clones (TH2, TH1) with varying TNF-alpha expression for functional assays.
- Employing bioassays and immunofluorescence to detect TNF-alpha.
- Assessed Mphi TNF-alpha gene expression and production following T cell contact.
Main Results:
- Anti-TNF-alpha confirmed to inhibit Mphi activation by activated T cells.
- T cell clones lacking detectable memTNF-alpha were equally effective in Mphi activation.
- Mphi activation peaked earlier than memTNF-alpha expression in a specific T cell clone.
- Activated T cells induced de novo TNF-alpha production and release by Mphi.
Conclusions:
- While TNF-alpha is crucial for Mphi activation, memTNF-alpha on T cells is not essential.
- Other T cell membrane molecules likely contribute to Mphi activation.
- These molecules may act by stimulating Mphi to produce TNF-alpha, leading to autocrine activation.
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