Tumor necrosis factor-α negatively regulates airway hyperresponsiveness through γδ T cells

Tumor necrosis factor (TNF)-α is a potent cytokine with immunomodulatory, proroinflammatory, and pathobiologic activities. Although TNF-α is thought to play a role in mediating airway inflammation and airway hyperresponsiveness (AHR), its function is not well defined. TNF-α - deficient mice and mice expressing TNF-α in their lungs because of a TNF-α transgene placed under the control of the surfactant protein (SP)-C promoter (SP-C/TNF-α - transgenic mice) were sensitized to ovalbumin (OVA) and subsequently challenged with OVA via the airways; airway function in response to inhaled methacholine was monitored. In the TNF-α - deficient mice, AHR was significantly increased over that in controls. In contrast, the transgenic mice failed to develop AHR. In addition, sensitized/challenged TNF-α - deficient mice had significantly increased numbers of eosinophils and higher levels of interleukin (IL)-5 and IL-10 in their bronchoalveolar lavage fluid than were found for control mice. However, in SP-C/TNF-α - transgenic mice, both the numbers of eosinophils and levels of IL-5 and IL-10 were significantly lower than in sensitized/challenged transgene-negative mice. γδ T cells have been shown to be activated by TNF-α and to negatively regulate AHR. Depletion of γδ T cells in the TNF-α - transgenic mice in the present study increased AHR, whereas depletion of these cells had no significant effect in TNF-α - deficient mice. These data indicate that TNF-α can negatively modulate airway responsiveness, controlling airway function in allergen-induced AHR through the activation of γδ T cells.