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

• 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
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.200939554

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.