Abstract
Adaptive immune responses require clonal expansion and differentiation of naive T cells into cytokine-secreting effector cells. After priming via signals through the T cell receptor, naive T helper cells express cytokine mRNA but do not secrete cytokine protein without additional T cell receptor stimulation. Here we show that primed T cells demonstrated phosphorylation of eukaryotic initiation factor 2-α (eIF2α), a 'collapsed' polysome profile, increased expression of stress-response genes and accumulation of cytoplasmic granules associated with RNA-binding proteins, all features of the integrated stress response. Restimulation of the cells resulted in rapid eIF2α dephosphorylation, ribosomal mRNA loading and cytokine secretion. Interference with the function of granule-associated proteins or accumulation of phosphorylated eIF2α enhanced release of interleukin 4 during T helper type 2 priming. Therefore, T lymphocytes require components of the integrated stress response to uncouple differentiation from the execution of effector functions.
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Acknowledgements
We thank Z. Wang, C. McArthur, N. Flores, J. Lin, L. Stowring and A. Barczak for technical support; R. Wek, W. Sha, N. Kedersha and P. Anderson for reagents; D. Ron and P. Walter for reagents and discussions; and J. Cyster for comments. Supported by the National Institutes of Health (AI30663 and HL56385 to R.M.L.), Deutsche Forschungsgemeinschaft (SCHE692/1-1 to S.S.), the Juvenile Diabetes Research Foundation–Irvington Institute (R.L.R.) and the Ellison Medical Foundation (R.M.L.).
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Supplementary information
Supplementary Fig. 1
Stable GFP expression in parked T cells marks IL-4 translation potential. (PDF 354 kb)
Supplementary Fig. 2
Overexpression of DM stress kinases reduces T cell viability. (PDF 228 kb)
Supplementary Table 1
Polysomal redistribution of mRNAs during restimulation of primed TH2 cells (PDF 134 kb)
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Scheu, S., Stetson, D., Reinhardt, R. et al. Activation of the integrated stress response during T helper cell differentiation. Nat Immunol 7, 644–651 (2006). https://doi.org/10.1038/ni1338
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DOI: https://doi.org/10.1038/ni1338
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