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Abstract: FR-PO1060

Classic IL-6R Signaling in CD4+ T Cells Directs Nephritogenic Th17 Responses and Enhances Treg Function

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation


  • Hagenstein, Julia, University Hospital Hamburg Eppendorf, Hamburg, Germany
  • Melderis, Simon, University Hospital Hamburg Eppendorf, Hamburg, Germany
  • Nosko, Anna, University Hospital Hamburg Eppendorf, Hamburg, Germany
  • Warkotsch, Matthias, University Hospital Hamburg Eppendorf, Hamburg, Germany
  • Richter, Johannes V., University Hospital Hamburg Eppendorf, Hamburg, Germany
  • Kluger, Malte A., University Hospital Hamburg Eppendorf, Hamburg, Germany
  • Steinmetz, Oliver M., University Hospital Hamburg Eppendorf, Hamburg, Germany

Group or Team Name

  • Steinmetz Lab

Th17 cells are central pathogenic mediators of glomerulonephritis (GN), while regulatory T cells (Tregs) mediate protection. The pleiotropic cytokine IL-6 was shown to modulate the function of both cell populations, but many aspects in this process remain unclear. These include the mode of IL-6 signaling responsible (classic, alternative or cluster), whether IL-6 effects are mediated in a cell intrinsic fashion or indirectly and finally the functional importance of T cell subtype specific IL-6R signaling for GN.


Selective abrogation of classic IL-6 signalling on T cells was achieved by generating quadruple transgenic CD4CrexIL-6Rafl/fl mice, harbouring flourochromes under control of the Foxp3 (FIR) and IL-10 promoters (Tiger). The NTN model of crescentic GN was studied in these mice and in Rag1-/- recipients after transfer of different CD4+ T cell populations.


Rag1-/- recipients of IL-6R deficient CD4+ T cells showed significantly and selectively reduced splenic and renal Th17 responses. In line, renal neutrophil recruitment was substantially diminished. Surprisingly, however, the course of NTN was not ameliorated. As one possible explanation, we found reduced Treg infiltration into recipient kidneys of IL-6R deficient CD4+ T cells. Additional studies in CD4CrexIL-6Rfl/flxFIRxTiger mice revealed, that production of anti-inflammatory IL-10 by Foxp3+ Tregs and Foxp3- Tr1 cells, was not affected by absence of IL-6R signaling. In a next step, we transferred Treg depleted CD4+ T cells into Rag1-/- mice and again studied NTN. Also in this setting, Th17 responses were strikingly reduced by lack of IL-6R signaling in CD4+ T cells. Importantly, however, in the absence of Tregs in both groups, NTN was significantly ameliorated in recipients of IL-6R deficient CD4+ Teff.


Our data indicate, that classic IL-6R signaling on T cells, induces nephritogenic Th17 reponses and aggravates crescentic GN. Surprisingly, however, classic IL-6R signaling also enhances Treg function via currently undefined pathways. Given the impact on potential IL-6R directed therapies, the underlying molecular mechanisms clearly need to be defined by further studies.


  • Government Support - Non-U.S.