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Abstract: PO1444

Activation of the Integrated Stress Response Regulates the Production of IL-17 in Tissue Resident Memory T Cells

Session Information

Category: Transplantation

  • 1901 Transplantation: Basic

Authors

  • Asada, Nariaki, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Ginsberg, Pauline, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Kaffke, Anna, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Peters, Anett, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Song, Ning, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Riedel, Jan-Hendrik, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Paust, Hans-Joachim, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Krebs, Christian F., University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Mittrücker, Hans-willi, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • Panzer, Ulf, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Background

CD4-positive T cells produce cytokines and play a central role in immunity. Tissue-resident memory T (Trm) cells remain in organs after infection and contribute to efficient host defense by immediate production of cytokines, such as IL-17A. More recently, it was demonstrated that Trm cells also promote autoimmunity. Therefore, the regulation of cytokine production by Trm cells is of great importance to achieve efficient host defense without excessive inflammation. However, the control mechanisms of cytokine production by Trm cells are not well understood.

Methods

Human and mouse T cells including renal Trm cells were analyzed by single cell RNA sequencing (scRNAseq), polysome profiling combined with bulk RNA sequencing, RT-PCR, flow-cytometry, immunocytochemistry, and mRNA FISH. Mouse models for Staphylococcus aureus infection and crescentic glomerulonephritis were used to induce and study Trm cells in vivo.

Results

Combined scRNAseq, polysome profiling and tissue signature analysis of human and mouse tissue samples revealed that resting CD4+ Trm cells in the kidney express IL17A mRNA but do not produce or secrete the cytokine protein without re-stimulation. Mechanistically, we demonstrate that the phosphorylation of eIF2a, a key feature of the integrated stress response (ISR) activation, resulted in recruitment of IL17A mRNA into stress granules, which are organelles crucial for regulating mRNA translation during ISR, thereby inhibiting mRNA translation in resting Trm cells. Finally, we show that re-stimulation of human renal Trm cells through T cell receptor resulted in eIF2a dephosphorylation, leading to efficient translation of IL17A mRNA and subsequent IL-17A secretion.

Conclusion

Tissue-resident memory CD4+ T cells in the kidney express high levels of IL-17A cytokine mRNA. Under homeostatic conditions the cytokine mRNA is stored in stress granules and not translated into protein. In contrast, these Trm cells rapidly produce IL-17A upon re-stimulation. Our study identifies a novel mechanism of how “poised Trm17 cells” use the integrated stress response - stress granules pathway to regulate IL-17A cytokine mRNA translation. Dysregulation of this pathway might have a pathogenic role in chronic relapsing and remitting inflammatory diseases.

Funding

  • Government Support – Non-U.S.