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