TNF-α is critical for antitumor but not antiviral T cell immunity in mice
Thomas Calzascia, Marc Pellegrini, Håkan Hall, Laurent Sabbagh, Nobuyuki Ono, Alisha R. Elford, Tak W. Mak, Pamela S. Ohashi
Thomas Calzascia, Marc Pellegrini, Håkan Hall, Laurent Sabbagh, Nobuyuki Ono, Alisha R. Elford, Tak W. Mak, Pamela S. Ohashi
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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 8

The exogenous administration of immunostimulatory factors rescues the proliferation of P14/TNF-α–/– T cells in PDLN of RIP(GP × Tag2)/TNF-α–/– mice.

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The exogenous administration of immunostimulatory factors rescues the pr...
CFSE-labeled naive P14 WT or P14/TNF-α–/– CD8+ T cells were adoptively transferred into the indicated RIP(GP × Tag2) hosts in combination with CD40 agonistic Ab or CD40 Ab and the TLR2 ligand Pam3. Proliferation of CFSE-labeled cells was assessed 3 days later in PDLN. Zebra plots were gated on CFSE+CD8+Vα2+ cells. The percentage in each plot indicates the proportion of dividing cells among the CFSE-labeled population. The data presented are representative of 3 independent experiments.