In patients with asthma, inflammation and airway hyperresponsiveness (AHR) are associated with the accumulation of CD8+ T cells in the lungs. Mouse models of asthma involve administering an allergen to the airway (sensitization), followed by a second exposure to allergen (challenge), which triggers AHR. Okamoto et al. previously showed that AHR was less severe in CD8–/– mice than in wild-type mice and could be restored by the transfer of CD8+ effector (TEFF), but not CD8+ central memory (TCM), T cells to the CD8–/– mice. In the current study, microarray analyses showed that Notch1 mRNA was more abundant in TEFF than in TCM cells. Notch receptors determine cell fate in developmental processes, including during T cell lineage commitment. Activation of Notch receptors by their ligands, members of the Delta-like and Jagged families, results in γ-secretase-dependent cleavage of the Notch intracellular domain (NICD), which translocates to the nucleus to activate target gene transcription. Stimulation of the T cell receptors of TEFF cells in vitro increased the abundance of NICD compared with that in untreated cells, as determined by Western blotting. When TEFF cells were treated in vitro with a γ-secretase inhibitor (GSI) before transfer to allergen-challenged CD8–/– mice, AHR was less severe than that in mice that received vehicle-treated TEFF cells. Finally, when allergen-sensitized wild-type mice were treated with an antibody against the Notch ligand Delta1 before allergen challenge, their AHR was less severe than that of control antibody-treated mice. Together, these data indicate a role for Notch signaling in the development of CD8+ T cell-mediated AHR and suggest Delta1 as a potential therapeutic target in the treatment of allergen-induced AHR.
M. Okamoto, K. Takeda, A. Joetham, H. Ohnishi, H. Matsuda, C. H. Swasey, B. J. Swanson, K. Yasutomo, A. Dakhama, E. W. Gelfand, Essential role of Notch signaling in effector memory CD8+ T cell-mediated airway hyperresponsiveness and inflammation. J. Exp. Med. 205, 1087-1097 (2008). [Abstract] [Full Text]