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Requirement for the p75 TNF- Receptor 2 in the Regulation of Airway Hyperresponsiveness by T Cells¹

Arihiko Kanehiro^*, Michael Lahn, Mika J. Mäkelä^*, Azzeddine Dakhama^*, Anthony Joetham^*, Yeong-Ho Rha^*, Willi Born and Erwin W. Gelfand^2,*

Departments of ^* Pediatrics and Immunology, Program in Cell Biology, National Jewish Medical and Research Center, Denver, CO 80206

In a recent study, we found that TNF- negatively regulates airway responsiveness through the activation of T cells. The biological activities of TNF- are mediated by two structurally related but functionally distinct receptors, p55 (TNFR1) and p75 (TNFR2), which are independently expressed on the cell surface. However, the relative importance of either TNFR in airway hyperresponsiveness (AHR) is unknown. To investigate the importance of these TNFRs in the development of allergen-induced AHR, p55-deficient and p75-deficient mice were sensitized to OVA by i.p. injection and subsequently challenged with OVA via the airways; airway responsiveness to inhaled methacholine was monitored. p75-deficient mice developed AHR to a similar degree as control mice. In contrast, p55-deficient mice, which were sensitized and challenged with OVA, failed to develop AHR. In p55-deficient mice, both the numbers of eosinophils and levels of IL-5 in bronchoalveolar lavage fluid were significantly lower than in sensitized/challenged control mice (p < 0.05). However, depletion of T cells resulted in significant increases in AHR in the p55-deficient mice, whereas no significant effect of T cell depletion was evident in the p75-deficient mice. These data indicate that, in the absence of TNFR1 (p55), where TNF- uses the p75 pathway exclusively, the development of AHR is regulated by T cells.

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