Tumor Necrosis Factor Receptor 1 Mediates Dendritic Cell Maturation and CD8 T Cell Response through Two Distinct Mechanisms

Tumor necrosis factor alpha (TNFα) and its two receptors (TNFR1 and 2) are known to stimulate dendritic cell (DC) maturation and T cell response. However, the specific receptor and mechanisms involved in vivo are still controversial. Here we show that in response to an attenuated mouse hepatitis virus (MHV) infection, DCs fail to mobilize and up-regulate CD40, CD80, CD86, and MHC class I in TNFR1−/− mice as compared to the wild-type and TNFR2−/− mice. Correspondingly, virus-specific CD8 T cell response was dramatically diminished in TNFR1−/− mice. Adoptive transfer of TNFR1-expressing DCs into TNFR1−/− mice rescues CD8 T cell response. Interestingly, adoptive transfer of TNFR1-expressing naïve T cells also restores DC mobilization and maturation and endogenous CD8 T cell response. These results show that TNFR1, not TNFR2, mediates TNFα stimulation of DC maturation and T cell response to MHV in vivo. They also suggest two mechanisms by which TNFR1 mediates TNFα-driven DC maturation: a direct effect through TNFR1 expressed on immature DCs and an indirect effect through TNFR1 expressed on naïve T cells.