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Abstract: TH-PO558

Targeting Tissue-Specific T Cell Plasticity by Pooled Single-Cell CRISPR Screening in Preclinical Mouse Models

Session Information

Category: Glomerular Diseases

  • 1401 Glomerular Diseases: From Inflammation to Fibrosis

Authors

  • Hellmig, Malte, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Riecken, Kristoffer, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Paust, Hans-Joachim, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Zhao, Yu, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Jauch-Speer, Saskia-L., Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Sivayoganathan, Varshi, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Liu, Shuya, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Wiech, Thorsten, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Huber, Tobias B., Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Bonn, Stefan, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Huber, Samuel, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Panzer, Ulf, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Krebs, Christian F., Universitatsklinikum Hamburg-Eppendorf, Hamburg, Hamburg, Germany
Background

Treatment of autoimmune diseases demands a shift from unspecific immunosuppression towards targeted therapies. This could be achieved by turning pro-inflammatory T helper cells into anti-inflammatory subsets. However, the molecular pathways involved in T cell plasticity and stability are not fully understood. Single cell CRISPR-screens are a powerful tool to simultaneously analyze the impact of multiple genes on cellular phenotypes.

Methods

By combining single cell gene expression analysis and T cell receptor sequencing, we uncover Th17 to Th1 cell plasticity in the human kidney in renal autoimmunity. To investigate the molecules involved in T cell plasticity in disease settings, we established in vivo single cell CRISPR droplet sequencing (iCROP-seq).

Results

By applying this technique to in vivo models of inflammatory diseases in the kidney and intestine, we demonstrate that CRISPR-induced alterations in T cell polarization can be identified and ranked according to corresponding transcriptional perturbations. In particular, we targeted pro-inflammatory Th17 cells in models of immune-mediated diseases and quantified polarization biases into Th1 and regulatory T cells.

Conclusion

iCROP-seq will facilitate the identification of therapeutic targets by highly efficient functional stratification of genes and pathways in a disease- and tissue-specific manner.

Funding

  • Government Support – Non-U.S.