Pathogenic T helper 17 (TH17) cells have been implicated in immune-mediated glomerular disease, whereas T regulatory (Treg) cells are known to have an anti-inflammatory and protective role. Now, Oliver M. Steinmetz and colleagues report on how IL-6 modulates T cell differentiation in a crescentic glomerulonephritis (GN) model.
“Targeting the IL-6–IL-6 receptor (IL-6R) axis has been successfully used to treat inflammatory diseases, but blocking IL-6 signalling aggravated experimental crescentic GN,” explains Steinmetz. To investigate this discrepancy, the researchers created CD4-specific Il6ra–/– mice. In their model of nephrotoxic nephritis (NTN) induced with nephrotoxic sheep serum, loss of IL-6Rα on CD4+ cells reduced TH17 cell differentiation and secretion of TH17 cytokines compared with wild-type controls.
To ensure that only CD4+ T cells were Il6ra–/– in their system, the researchers adoptively transferred T cells into Rag1–/– (T cell-deficient) mice before inducing NTN. Compared with mice that received wild-type CD4+ T cells, recipients of Il6ra–/– CD4+ T cells had lower frequencies of splenic and renal TH17 cells, and a significantly reduced kidney neutrophil infiltrate, but renal outcomes did not improve. Inhibiting the TH17 cell response by blocking IL-6R signalling on all CD4+ T cells was thus not effective in protecting the kidney from damage. Moreover, when only Treg cells were deficient for IL-6Rα among the transferred CD4+ T cells, renal outcomes were significantly worse compared with animals that received wild-type Treg cells, despite a similar TH17 cell response. These findings suggest a protective role for IL-6-dependent Treg cells, which are enriched for RORγt+FOXP3+CCR6+ Treg cells.
“Our data revise the paradigm of IL-6 as a ‘pro-inflammatory master switch’ — we show that classic IL-6 signalling induces both pathogenic TH17 cells and protective RORγt+FOXP3+ Treg cells, which have an enhanced suppressive capacity,” concludes Steinmetz.
Hagenstein, J. et al. A novel role for IL-6 receptor classic signaling: induction of RORγt+Foxp3+ Tregs with enhanced suppressive capacity. J. Am. Soc. Nephrol. 30, 1439–1453 (2019)
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Wang, M. IL-6-dependent regulatory T cells in GN. Nat Rev Nephrol 15, 662 (2019). https://doi.org/10.1038/s41581-019-0193-9