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Activation of the integrated stress response during T helper cell differentiation

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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Figure 1: Cytokine mRNA and protein expression are dissociated in primed TH2 cells from IL-4 (4get) and IFN-γ (Yeti) reporter mice.
Figure 2: Polysome analysis of primed and restimulated TH2 cells.
Figure 3: Increased phosphorylation of eIF2α serine 51 in TH2 cells after priming.
Figure 4: Expression of stress response–induced genes and the presence of TIA-1-associated granules in naive and TH2-primed CD4+ T cells.
Figure 5: Expression of dominant negative TIA-1 or constitutively active GADD34 in T cells during TH2 priming potentiates IL-4 secretion.

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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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Correspondence to Richard M Locksley.

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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)

Supplementary Methods (PDF 112 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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