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Abstract: SA-OR29

Targeting the Integrated Stress Response Pathway in T Cells Ameliorates Crescentic Glomerulonephritis in Mice

Session Information

Category: Glomerular Diseases

  • 1302 Glomerular Diseases: Immunology and Inflammation

Authors

  • Asada, Nariaki, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Ginsberg, Pauline, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Kaffke, Anna, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Peters, Anett, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Paust, Hans-Joachim, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Krebs, Christian F., Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Mittrücker, Hans-willi, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Panzer, Ulf, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
Background

CD4+ T cells play a central role in immunity by producing cytokines. After infection, some T cells remain in organs and become tissue-resident memory T (Trm) cells, which contribute to efficient host defense by immediate production of cytokines. Recently, it was demonstrated that Trm cells are also associated with autoimmune disease development and relapse. Therefore, tight regulation of cytokine production by Trm cells is of great importance to achieve efficient host defense without excessive inflammation. However, the underlying mechanisms of cytokine production by Trm cells are not well characterized.

Methods

Human and murine T cells in the kidney were analyzed by single cell RNA sequencing (scRNAseq), polysome profiling, 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

scRNAseq analysis of T cells from human healthy kidney revealed that Trm cells express high mRNA levels of proinflammatory cytokines such as IL17A, INFG, and CSF2. However, flow-cytometry, tissue signature analysis, and polysome profiling showed that Trm cells do not translate cytokine mRNA into protein without re-stimulation. Mechanistically, we demonstrated that the phosphorylation of eIF2a, a key feature of the integrated stress response (ISR) activation, results in recruitment of cytokine mRNA into stress granules, which are organelles crucial for regulating mRNA translation during ISR. Re-stimulation of Trm cells resulted in eIF2a dephosphorylation, leading to rapid translation of cytokine mRNA into protein. Moreover, we found that blocking eIF2a phosphatase by Raphin1 efficiently suppresses eIF2a dephosphorylation and cytokine production from Trm cells. In vivo administration of Raphin1 improved crescent formation and albuminuria in immune-mediated kidney injury in mice.

Conclusion

CD4+ Trm cells express high level cytokine mRNA but regulate translation through ISR under homeostatic conditions. Targeting ISR by Raphin1 suppresses cytokine production from activated Trm cells and autoimmune kidney disease progression in mice. Our study identifies a novel mechanism of how ISR regulates rapid cytokine production of poised Trm cells in health and disease.

Funding

  • Government Support – Non-U.S.