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Abstract: TH-OR051

IL-17 Signaling in CD4+ T Cells Control TH17 Responses

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Schmidt, Tilman, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
  • Kapffer, Sonja, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
  • Krebs, Christian F., Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
  • Paust, Hans-Joachim, Hamburg University Hospital, Hamburg, Germany
  • Panzer, Ulf, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
Background

The interleukin-17 family (IL-17A-F) plays a critical role in autoimmune and chronic inflammatory diseases, such as crescentic GN. A heterodimeric receptor complex consisting of IL-17RA and a ligand specific IL-17 receptor subunit (IL-17RB-E), which is expressed by epithelial and endothelial tissue cells, mediates their biological effects. In contrast, the IL-17 receptor expression pattern and function on hematopoietic cells, e.g. CD4+ T cell subsets, remains to be determined.

Methods

Crescentic GN (Nephrotoxic Nephritis, NTN) was induced in IL-17A, IFNγ and Foxp3 triple-reporter mice for in vivo cell sorting of renal CD4+ T cell subsets and subsequent single cell RNAseq of CD4+ T cells using the 10X Single Cell system. The effect of IL-17 signaling in CD4+ T cells was analyzed by CD4 T cell polarization experiments. Moreover, we generated TH17 cell specific IL-17RA gene-deficient mice to study the role of IL-17 signaling in Th17 cells in the NTN model.

Results

mRNA expression analysis of sorted T cells revealed a predominant expression of IL-17RC and IL-17RE by IL-17Apositive TH17 cells, high IL-17RB expression by Foxp3positiveTregs, whereas IL-17RA is ubiquitously expressed by all CD4+ T-cell subsets, demonstrating for the first time a T cell specific expression pattern of IL-17 receptors. In vitro T cell polarization experiments revealed that IL-17A-RC signaling downregulates IL-17A expression of TH17 cells. In line, competitive adoptive transfer experiments of wildtype and IL-17RA-/- CD4+ T cells into nephritic Rag1-/- mice revealed that TH17 genes were upregulated in cells lacking the IL-17RA, indicating that IL-17 signaling on CD4+ T-cells is instrumental for the control of the TH17 response. In addition, scRNAseq analysis of 12,971 renal CD4+ T cells revealed that, TH17 cells lacking the IL-17RA form a distinct cluster which is characterized by upregulation TH17 marker genes. Most importantly, mice lacking IL-17 signaling specifically in TH17 cells demonstrated dysregulation of TH17 immune response with higher production of IL-17A and F after induction of NTN and an accelerated course of the disease.

Conclusion

Our findings indicate that IL-17 receptor signaling in CD4 T cells control TH17 immune response via a self-inhibitory loop. These findings might provide new insight into the development of more efficient anti-TH17 treatment strategies.

Funding

  • Government Support - Non-U.S.