Soluble TNF-α but not transmembrane TNF-α sensitizes T cells for enhanced activation-induced cell death

In addition to its proinflammatory effects, TNF-α exhibits immunosuppression. Here, we compared the capacities of transmembrane TNF-α (tmTNF) and soluble TNF-α (sTNF) in regulating expansion of activated T cells by apoptosis. Splenic CD4⁺ T cells from wtTNF, TNF-α-deficient (TNF⁻/⁻) and TNF⁻/⁻ mice...

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Published in:European journal of immunology 2009-11, Vol.39 (11), p.3171-3180
Main Authors: Müller, Stefan, Rihs, Silvia, Dayer Schneider, Johanna M, Paredes, Bruno E, Seibold, Ingeborg, Brunner, Thomas, Mueller, Christoph
Format: Article
Language:English
Subjects:
Activation‐induced cell death
Adoptive Transfer
Animals
Apoptosis - immunology
CD4+ T cells
Cell Proliferation
Cell Separation
Colitis
Colitis - immunology
Flow Cytometry
Immunomodulation - immunology
Lymphocyte Activation - immunology
Mice
Mice, Inbred C57BL
Mice, Knockout
T-Lymphocytes - immunology
TNF‐a
Transmembrane TNF
Tumor Necrosis Factor-alpha - immunology
Tumor Necrosis Factor-alpha - metabolism
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Summary:In addition to its proinflammatory effects, TNF-α exhibits immunosuppression. Here, we compared the capacities of transmembrane TNF-α (tmTNF) and soluble TNF-α (sTNF) in regulating expansion of activated T cells by apoptosis. Splenic CD4⁺ T cells from wtTNF, TNF-α-deficient (TNF⁻/⁻) and TNF⁻/⁻ mice expressing a non-cleavable mutant tmTNF showed comparable proliferation rates upon TCR-mediated stimulation. Activation-induced cell death (AICD), however, was significantly attenuated in tmTNF and TNF⁻/⁻, compared with wtTNF CD4⁺ T cells. Addition of sTNF during initial priming was sufficient to enhance susceptibility to AICD in tmTNF and TNF⁻/⁻ CD4⁺ T cells to levels seen in wtTNF CD4⁺ T cells, whereas addition of sTNF only during restimulation failed to enhance AICD. sTNF-induced, enhanced susceptibility to AICD was dependent on both TNF receptors. The reduced susceptibility of tmTNF CD4⁺ T cells for AICD was also evident in an in vivo model of adoptively transferred CD4⁺ T-cell-mediated colonic inflammation. Hence, the presence of sTNF during T-cell priming may represent an important mechanism to sensitize activated T cells for apoptosis, thereby attenuating the extent and duration of T-cell reactivities and subsequent T-cell-mediated, excessive inflammation.
ISSN:0014-2980
1521-4141
DOI:10.1002/eji.200939554