Abstract: TH-PO049

CD4+ T Cells Control TH17 Responses in an IL-17 Receptor A-Dependent Manner

Session Information

Category: Glomerular

  • 1001 Glomerular: Basic/Experimental Immunology and Inflammation

Authors

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

The characterization of IL-17A producing CD4+ TH17 cells has substantially improved our understanding of organ-specific autoimmunity including crescentic glomerulonephritis. The biological effects of IL-17A are mediated via the IL-17 receptor A. Recent clinical trials targeting the IL-17 signaling pathway by IL-17RA antibodies, have been remarkable effective for the treatment of some autoimmune disorders (psoriasis) but even led to the exacerbation of colitis in patients with inflammatory bowel diseases. The reason for these controversial results are unknown.

Methods

We generated conventional and conditional IL-17RA deficient mice to analyze the effect of IL-17 signaling in models of inflammatory kidney and gut diseases. Cytokine production was analyzed using multi-color flow cytometry.

Results

Using the TH17 dependent model of crescentic GN (nephrotoxic nephritis), we found that IL-17RA gene-deficiency, as well as IL-17RA antibody treatment, did not ameliorated the clinical course of the GN in terms of glomerular crescent formation, albuminuria, and renal function. Of note, Citrobacter rodentium induced colitis, that triggers a potent TH17 cell response in the gut, was significantly aggravated in IL-17RA-/- mice. Mechanistically, we identified a unique pattern of dysregulated CD4 T cell immunity in these animals. Production of IL-17A, IL-17F and in particular the TH17 associated cytokines IL-22 and GM-CSF were highly upregulated in the inflamed organs accompanied by tissue injury in the absence of IL-17 signaling. 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. Using IL-17A reporter mice and cell-specific IL-17RA-/- mice we finally demonstrated, that IL-17RA is highly expressed by CD4+ TH17 cells and that this expression is critical for the control of the TH17 response and subsequent tissue injury in crescentic GN and colitis.

Conclusion

Our findings indicate that IL-17RA expression on CD4 T cells control TH17 immune response and production of IL-22 and GM-CSF via a self-inhibitory loop. This knowledge might help to understand organ specific outcome after anti-IL-17RA antibody treatment in immune-mediated disorders and indicate that IL-17RA blockade might be ineffective for treatment of RPGN or colitis.

Funding

  • Government Support - Non-U.S.