Unfolded Protein Response Factor ATF6 Augments T Helper Cell Responses and Promotes Mixed Granulocytic Airway Inflammation

The unfolded protein response (UPR) is associated with the risk of asthma, including treatment- refractory severe asthma. Several recent studies demonstrated a pathogenic role of activating transcription factor 6α (ATF6α or ATF6), one of the essential arms of UPR, in airway structural cells. However, its role in T helper (TH) cells has not been well examined. In this study, we found that ATF6 was selectively induced by STAT6 and STAT3 in TH2 and TH17 cells, respectively. ATF6 upregulated UPR genes and promoted the differentiation and cytokine secretion of TH2 and TH17 cells. T cell-specific Atf6 -deficiency impaired TH2 and TH17 responses in vitro and in vivo and attenuated mixed granulocytic experimental asthma. ATF6 inhibitor Ceapin A7 suppressed ATF6 downstream gene expression and TH cell cytokine expression in both murine and human memory CD4 + T cells. At the chronic stage of asthma, administration of Ceapin A7 lessened TH2 and TH17 responses in vivo , leading to alleviation of both airway neutrophilia and eosinophilia. Thus, our results demonstrate a critical role of ATF6 in TH2 and TH17 cell-driven mixed granulocytic airway disease, suggesting a novel option to combat steroid-resistant mixed and even T2-low endotypes of asthma by targeting ATF6.