TY - JOUR
T1 - TNF-α is critical for antitumor but not antiviral T cell immunity in mice
AU - Calzascia, Thomas
AU - Pellegrini, Marc
AU - Hall, Håkan
AU - Sabbagh, Laurent
AU - Ono, Nobuyuki
AU - Elford, Alisha R.
AU - Mak, Tak W.
AU - Ohashi, Pamela S.
PY - 2007/12
Y1 - 2007/12
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI32567
DO - 10.1172/JCI32567
M3 - Article
C2 - 17992258
AN - SCOPUS:36448978124
VL - 117
SP - 3833
EP - 3845
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 12
ER -