|Budget Amount *help
¥3,900,000 (Direct Cost: ¥3,900,000)
Fiscal Year 2004: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2003: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2002: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2001: ¥1,300,000 (Direct Cost: ¥1,300,000)
Mice exposed to aerosolized ovalbumin(OVA) develop increased airway hyperresponsiveness(AHR) when deficient in γδ T cells. This finding suggests that γδ T cells function as negative regulators. The regulatory influence of γδ T cells is evident after OVA-sensitization and -challenge, and after OVA-challenge alone, but not in untreated mice. With aerosolized Abs to target pulmonary T cells, we now demonstrate that negative regulation of airway responsiveness is mediated by a small subpopulation of pulmonary γδ T cells.
TNF-α is a potent cytokine with immunomodulatory, proinflammatory and pathobiological activities. Although TNF-α is thought to play a role in mediating airway hyperresponsiveness in asthma, its function is not defined. Depletion of γδ T cells in the TNF-α transgenic mice increased AHR, whereas this depletion 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.
The biological activities of TNF-α are mediated by two structurally related but functionally distinct receptors, p55 (TNFR1) and p75 (TNFR2), which are independently expressed on the cell surface. Depletion of γδ T cells resulted in significant increases in AHR in the p55-deficient mice, whereas no significant effect of γδ T cells depletion was evident in the p75-deficient mice. These data indicate that, in the absence of p55, where TNF-α uses the p75 pathway exclusively, the development of AHR is regulated by γδ T cells.
γδ T cells express Vγ4 and depend in their function on the presence of IFN-γ and MHC class I. Moreover, their effect can be demonstrated in the absence of αβ T cells. This novel type of negative regulation seems to precede the development of the adaptive, antigen-specific allergic response.