Kidney Week

Abstract: SA-PO585

IL-17 Signaling in CD4⁺ T Cells Controls TH17 Immune Response

Session Information

• Glomerular Diseases: Immunology, Inflammation - II
  November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1202 Glomerular Diseases: Immunology and Inflammation

Authors

• Schmidt, Tilman, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Tilman Schmidt,

• Lübbe, Jonas, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Jonas Lübbe,

• Riedel, Jan-Hendrik, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Jan-Hendrik Riedel,

• Kilian, Christoph, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Christoph Kilian,

• Krebs, Christian F., University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Christian F. Krebs,

• Paust, Hans-Joachim, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Hans-Joachim Paust,

• Panzer, Ulf, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Ulf Panzer,

Background

The IL-17/IL-17 receptor system plays a crucial role in autoimmune and chronic inflammatory diseases. The biological effects on residential cells are mediated through a heterodimeric receptor complex consisting of IL-17RA and a ligand specific IL-17 receptor subunit (IL-17RB - IL-17RE). However, the expression and function of IL-17 receptors on hematopoietic cells as CD4⁺ T cells have not been elucidated.

Methods

Crescentic GN (NTN), Psoriasis and C. rodentium colitis were induced in IL-17RA^-/-, IL-17RC^-/- and in IL-17A, IFNγ and Foxp3 triple-reporter mice for in vivo cell sorting of CD4⁺ T cell subsets. Single cell RNAseq of CD4⁺ T cells from the nephritic kidney was performed using the 10X single cell system. pLIVE-plasmid was used to induce IL-17A overexpression in vivo. Moreover, we generated T_H17 cell specific IL-17RA gene-deficient mice to study the role of IL-17 signaling in T_H17 cells in the NTN model.

Results

Induction of inflammation in the kidney, skin and intestine in IL-17RA^-/- mice resulted in an aggravated T_H17 cell immune response. Transfer of IL-17RA^-/- bone marrow cells in irradiated WT mice indicated IL-17 signaling on hematopoietic cells. CD4⁺ IL-17 producing WT cells from the inflamed kidney, analyzed with single cell RNAseq, demonstrated a highly activated IL-17 signaling score. mRNA expression analysis of FACS-sorted T cells revealed predominant expression of IL-17RC and IL-17RE by IL-17A⁺ T_H17 cells, whereas IL-17RA is ubiquitously expressed by all CD4⁺ T cell subsets, demonstrating a T cell specific expression pattern of IL-17 receptors. Systemic overexpression of IL-17A showed a reduction of CD4⁺ IL-17A⁺ cells in the kidneys of nephritic mice. Moreover, competitive adoptive transfer experiments of wildtype and IL-17RA^-/- or IL-17RC^-/- CD4⁺ T cells into nephritic Rag1^-/- mice showed that IL-17 signaling on CD4⁺ T cells is critically for the control of the pathogenic T_H17 response. Mice specifically lacking the IL-17RA receptor in IL-17A⁺ cells also present an enhanced T_H17 cell immune response.

Conclusion

Our findings indicate intrinsic IL-17RA/RC signaling on CD4⁺ T cells, which regulates the T_H17 cell immune response. This novel mechanism might lead to more efficient therapeutic options in targeting IL-17 signaling pathways.