The integrated stress response/eIF2a pathway controls cytokine production in tissue-resident memory CD4⁺T cells

Abstract

Tissue-resident memory T (Trm) cells are a specialized T cell population that resides in tissues and can play both a protective and pathogenic role. The mechanism that enables Trm cells to provide a rapid protective response while restricting their function in homeostasis remains unclear. Here, we show that human and mouse CD4+Trm cells exist in a poised state, characterized by storage of proinflammatory type-1 and type-3 cytokine mRNAs without protein production. In steady-state conditions, cytokine mRNA translation in Trm cells is suppressed by the integrated stress response (ISR)/eIF2α pathway, whereas Trm-cell activation under inflammatory conditions results in eIF2α dephosphorylation, leading to derepression and rapid translation of the cytokine mRNAs stored in stress granules. Pharmacological inhibition of eIF2α dephosphorylation resulted in reduced cytokine production from Trm cells, and ameliorated autoimmune kidney disease in mice. Consistent with these results, the ISR pathway in Trm cells was downregulated in patients with immune-mediated diseases of the kidney and the intestine. Our results identify ISR/eIF2α-mediated control of cytokine mRNA translation as an underlying mechanism that restricts Trm cell activity in homeostasis but also promotes rapid response upon local infection or autoimmune reaction.