Asthma is a chronic inflammatory disease of the airways that affects 26 million Americans and results in approximately 3600 deaths per year in the US alone (1a). Asthma is a heterogeneous disease and both Th2 predominant and Th17 predominant forms have been described with different etiologies. Interestingly, it was recently determined that a subset of patients with particularly severe asthma contain T cells that make both Th2 and Th17 cytokines. However, mechanisms that prevent allergen specific T cells from becoming Th2/17 dual producers have not been described. We have identified a novel inhibitory pathway that limits the differentiation and pathogenicity of both Th2, Th9 and Th2/17 dual-producing T cells and protects against airway remodeling in mice. This pathway is controlled by the E3 ubiquitin ligase Cul5. Supporting this, we recently generated mice in which Cul5 was deleted only in T cells, and determined that Cul5 limits the numbers of Th2, Th9 and Th2/17 dual cytokine producing T cells and airway remodeling after house dust mite exposure. Specifically, we found that mice lacking Cul5 in T cells showed increased lung inflammation, eosinophilia, goblet cell hyperplasia and fibrosis, as well as AHR. Using a screen to reveal Cul5 binding partners, we identified Traid1, a RING-between- RING E3 ubiquitin ligases that was recently shown to be important for Cul5 activity. Based on these preliminary data we hypothesize that Cul5 works with Triad1 to limit the numbers of pathogenic T cells to prevent asthma. Our long term goal is to develop novel therapeutic strategies that activate the Cul5 pathway to turn T cells off in patients with asthma. However, to do this effectively we must first determine how Cul5 activity is regulated. In this proposal we will determine whether mice with a deletion of Traid1 in T cells develop a similar inflammation and airways remodeling following HDM exposure as we observed in Cul5fl/flCD4-Cre animals. This would indicate that regulating the interaction between Cul5 and Triad1 might be a good therapeutic approach.
Based on our discovery that Cul5 becomes activated following T cell activation and is required to limit T cell activation and the numbers of cytokine producing CD4 T cells, we now propose studies that will reveal the mechanistic underpinnings of how Cul5 functions with Triad1 in T cells. Such information will aid the rational design of therapies that target Cul5 activity.
