Group 3 innate lymphoid cells (ILC3s) are the innate counterparts of Th17 that require the transcription factor RORγt for development and contribute to the defense against pathogens through IL-22 and IL-17 secretion. Proliferation and effector functions of Th17 require a specific mTOR-dependent metabolic program that utilizes high-rate glycolysis, while mitochondrial lipid oxidation and production of reactive oxygen species (mROS) support alternative T reg cell differentiation. Whether ILC3s employ a specific metabolic program is not known. Here, we find that ILC3s rely on mTOR complex 1 (mTORC1) for proliferation and production of IL-22 and IL-17A after in vitro activation and Citrobacter rodentium infection. mTORC1 induces activation of HIF1α, which reprograms ILC3 metabolism toward glycolysis and sustained expression of RORγt. However, in contrast to Th17, ILC3 activation requires mROS production; rather than inducing an alternative regulatory fate as it does in CD4 T cells, mROS stabilizes HIF1α and RORγt in ILC3s and thereby promotes their activation. We conclude that ILC3 activation relies on a metabolic program that integrates glycolysis with mROS production.

Chronic infections and cancer cause T cell dysfunction known as exhaustion. This cell state is caused by persistent antigen exposure, suboptimal co-stimulation and a plethora of hostile factors that dampen protective immunity and limit the efficacy of immunotherapies^1,2,3,4. The mechanisms that underlie T cell exhaustion remain poorly understood. Here we analyse the proteome of CD8⁺ exhausted T (T_ex) cells across multiple states of exhaustion in the context of both chronic viral infections and cancer. We show that there is a non-stochastic pathway-specific discordance between mRNA and protein dynamics between T effector (T_eff) and T_ex cells. We identify a distinct proteotoxic stress response (PSR) in T_ex cells, which we term T_ex-PSR. Contrary to canonical stress responses that induce a reduction in protein synthesis^5,6, T_ex-PSR involves an increase in global translation activity and an upregulation of specialized chaperone proteins. T_ex-PSR is further characterized by the accumulation of protein aggregates and stress granules and an increase in autophagy-dominant protein catabolism. We establish that disruption of proteostasis alone can convert T_eff cells to T_ex cells, and we link T_ex-PSR mechanistically to persistent AKT signalling. Finally, disruption of T_ex-PSR-associated chaperones in CD8⁺ T cells improves cancer immunotherapy in preclinical models. Moreover, a high T_ex-PSR in T cells from patients with cancer confers poor responses to clinical immunotherapy. Collectively, our findings indicate that T_ex-PSR is a hallmark and a mechanistic driver of T cell exhaustion, which raises the possibility of targeting proteostasis pathways as an approach for cancer immunotherapy.