TNF-alpha-dependent maturation of local dendritic cells is critical for activating the adaptive immune response to virus infection

Tumor necrosis factor-alpha (TNF-alpha) is well recognized for its role in mediating innate immune responses. However, the mechanisms of TNF-alpha tha t influence the adaptive immune response to virus infections are not well u nderstood. In this study, we have investigated the role of TNF-alpha in act ivating the cellular and humoral responses to systemic viral challenge with recombinant replication-defective adenovirus (rAd). Evaluation of T cell f unction in TNF-alpha -deficient (TNFKO) mice revealed impaired virus-specif ic proliferation of T cells derived from the draining lymph nodes of the li ver. Analysis of dendritic cells (DC) isolated from local draining lymph no des after systemic challenge showed that DC from TNFKO mice were relatively immature compared with those from strain-matched wild-type mice. In vitro, TNF-alpha was required to mature DC efficiently during virus-mediated stim ulation. Adoptive transfer of primed, mature DC into TNFKO mice restored T cell responses and reconstituted anti-adenovirus antibody responses. Thus, TNF-alpha plays a significant role in the maturation of DC after adenovirus challenge both in vitro and in vivo, highlighting the importance of this i nnate cytokine in activating adaptive immunity to viral challenge.