Th17 cells differentiated for 72 h in the presence of vehicle or AA147

ABSTRACT: The differentiation of naïve CD4+ T cells into helper T cell (TH) subsets such as TH1, TH2, TH17 and TREG cells is governed by tightly coordinated activation programmes dependent on T cell receptor (TCR) engagement, co-stimulation, and cytokine signalling. This differentiation process also involves the regulation of stress-responsive signalling pathways such as the unfolded protein response (UPR) and the oxidative stress response (OSR) to adapt to the physiologic demands specific to distinct TH cell subset functions. This suggests that pharmacologically targeting stress-responsive signalling pathways offers a unique opportunity to selectively remodel the differentiation of these different T cell subsets. We previously identified compound AA147 as a metabolically activated proteostasis regulator that can induce both the ATF6 signalling arm of the UPR and, in certain cell types, the NRF2-regulated arm of the OSR.(Paxman et al., 2018; Plate et al., 2016) Here, we show that treatment with AA147 selectively reduces differentiation of pro-inflammatory TH17 cells by promoting degradation of the lineage-specifying transcription factor RORt, without impacting the transcription factors of other T helper cell subsets. AA147-dependent reduction in TH17 differentiation is independent of ATF6 activation but instead involves activation of NRF2, which reduces intracellular reactive oxygen species (ROS) to hinder TH17 cell differentiation. Apart from RORt, we also found that AA147 decreases expression of the TCR-responsive factor IRF4, thus suppressing production of select effector cytokines across TH cells, demonstrating additional ways in which this compound reshapes the activities of these essential T cell subsets. Our results demonstrate the potential for metabolically activated proteostasis regulators such as AA147 to selectively reshape TH17 cell identity while broadly dampening effector cytokine responses across TH cell subsets, through both NRF2-dependent and independent mechanisms during T cell differentiation.

ORGANISM(S): Mus musculus

PROVIDER: GSE344840 | GEO | 2026/09/01

REPOSITORIES: GEO