TNF-α is critical for antitumor but not antiviral T cell immunity in mice
Thomas Calzascia, … , Tak W. Mak, Pamela S. Ohashi
Thomas Calzascia, … , Tak W. Mak, Pamela S. Ohashi
Published November 8, 2007
Citation Information: J Clin Invest. 2007;117(12):3833-3845. https://doi.org/10.1172/JCI32567.
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Research Article Immunology

TNF-α is critical for antitumor but not antiviral T cell immunity in mice

Abstract

TNF-α antagonists are widely used in the treatment of inflammatory and autoimmune diseases, but their use is associated with reactivation of latent infections. This highlights the importance of TNF-α in immunity to certain pathogens and raises concerns that critical aspects of immune function are impaired in its absence. Unfortunately, the role of TNF-α in the regulation of T cell responses is clouded by a myriad of contradictory reports. Here, we show a role for TNF-α and its receptors, TNFR1 and TNFR2, specifically in antitumor immunity. TNF-α–deficient mice exhibited normal antiviral responses associated with strong inflammation. However, TNF-α/TNFR1–mediated signals on APCs and TNF-α/TNFR2 signals on T cells were critically required for effective priming, proliferation, and recruitment of tumor-specific T cells. Furthermore, in the absence of TNF-α signaling, tumor immune surveillance was severely abrogated. Finally, treatment with a CD40 agonist alone or in combination with TLR2 stimuli was able to rescue proliferation of TNF-α–deficient T cells. Therefore, TNF-α signaling may be required only for immune responses in conditions of limited immunostimulatory capacity, such as tumor surveillance. Importantly, these results suggest that prolonged continuous TNF-α blockade in patients may have long-term complications, including potential tumor development or progression.

Authors

Thomas Calzascia, Marc Pellegrini, Håkan Hall, Laurent Sabbagh, Nobuyuki Ono, Alisha R. Elford, Tak W. Mak, Pamela S. Ohashi

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Figure 4

TNF-α/TNFR2–related T cell–intrinsic defects result in defective cytokine production.

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TNF-α/TNFR2–related T cell–intrinsic defects result in defective cytokin...
(A) P14 WT, P14/TNFR1–/–, P14/TNFR2–/–, or P14/TNF-α–/– CD8+ T cells were cocultured with GP33-pulsed thioglycollate-induced macrophages for 4 hours in the presence of an inhibitor of intracellular protein transport. Following incubation, P14 cells were harvested, and the levels of intracellular TNF-α, IL-2, and IFN-γ were evaluated by intracellular flow cytometry. Representative contour plots for IL-2 and TNF-α are shown. The proportion of cells in each quadrant is also indicated. (B) Kinetics of TNF-α, IL-2, and IFN-γ production by P14 WT, P14/TNFR1–/–, P14/TNFR2–/–, or P14/TNF-α–/– CD8+ T cells stimulated as described in A. Mean values ± SEM from 4 independent experiments are shown. Statistically significant differences at 4 hours are indicated. For TNF-α, *P = 0.0249, **P = 0.0001. For IL-2, *P = 0.0048, **P = 0.0273. For IFN-γ, *P = 0.0122, **P < 0.0001, ***P = 0.0003.