Metabolically Activated Proteostasis Regulators Reduce Differentiation of CD4+ TH17 Cells

The differentiation of naive CD4+ T cells into effector T cell 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 involves 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 T cell subset functions. This suggests that pharmacologically targeting stress-responsive 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 RORgammat, without impacting the transcription factors of other CD4+ T cell subsets. AA147-dependent reduction in TH17 differentiation is independent of ATF6 activation and involves activation of NRF2, which reduces intracellular reactive oxygen species (ROS) to hinder TH17 cell differentiation. Apart from RORgammat, we found that AA147 decreases expression of the TCR-responsive factor IRF4, thus suppressing production of select effector cytokines across effector T 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 effector T cell subsets, through both NRF2-dependent and independent mechanisms during T cell differentiation.