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 1

The absence of TNF-α does not alter the kinetics or magnitude of LCMV-induced autoimmune diabetes in RIP-GP or P14/RIP-GP animals.

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The absence of TNF-α does not alter the kinetics or magnitude of LCMV-in...
(A) RIP-GP mice were infected with LCMV Arm. Blood glucose levels were measured at multiple time points and used as an indication of islet β cell autoimmune destruction. Blood glucose levels of 1 mouse representative of at least 6 mice are shown for each genotype. (B) P14/RIP-GP animals were infected with LCMV Arm, and blood glucose was monitored as in A. Blood glucose levels of 1 mouse representative of at least 5 mice are shown for each genotype. (C) CFSE-labeled P14 WT or TNF-α–/– CD8+ T cells were adoptively transferred into WT or TNF-α–/– mice infected 3 days previously with LCMV Arm. The extent of T cell proliferation was assessed by CFSE dilution in spleens 3 days later (solid lines). Histograms are gated on CFSE+CD8+Vα2+ cells and are representative of 3 independent animals per condition. Dashed lines indicate the CFSE profile of undivided cells. (D) Expression of CD69, CD44, and CD62L on CFSE+CD8+Vα2+ cells from C.