The integrated stress response pathway controls cytokine production in tissue-resident memory CD4+ T cells
Year: 2025
Type: article
Abstract: Tissue-resident memory T (T RM ) cells are a specialized T cell population that reside in tissues and provide a rapid protective response upon activation. Here, we showed that human and mouse CD4 + T RM cells existed in a poised state and stored messenger RNAs encoding proinflammatory cytokines without protein production. At steady state, cytokine mRNA translation in T RM cells was suppressed by the integrated stress response (ISR) pathway. Upon activation, the central ISR regulator, eIF2α, was dephosphorylated and stored cytokine mRNA was translated for immediate cytokine production. Genetic or pharmacological activation of the ISR–eIF2α pathway reduced cytokine production and ameliorated autoimmune kidney disease in mice. Consistent with these results, the ISR pathway in CD4 + T RM cells was downregulated in patients with immune-mediated diseases of the kidney and the intestine compared to healthy controls. Our results indicated that stored cytokine mRNA and translational regulation in CD4 + T RM cells facilitate rapid cytokine production during local immune response.
Source: Nature Immunology
Authors: Nariaki Asada, Pauline Ginsberg, Hans-Joachim Paust, Ning Song, Jan-Hendrik Riedel, Jan-Eric Turner, Anett Peters, Anna Kaffke, Jonas Engesser, Huiying Wang, Yu Zhao, Robin Khatri, Philipp Gild, Roland Dahlem, Björn-Philipp Diercks, Sarada Das, Zoya Ignatova, Tobias B. Huber, Immo Prinz, Nicola Gagliani, Hans-Willi Mittrücker, Christian F. Krebs, Ulf Panzer
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
Award: G1330611446
OpenAlex ID: W4408201414