IL-10 Receptor Signaling Empowers Regulatory T Cells to Control Th17 Responses and Protect from GN.

Th17 cells are central pathogenic mediators of autoimmune disease, including many forms of GN. IL-10 receptor signaling (IL-10R) in regulatory T cells (Tregs) has been implicated in the downregulation of Th17 cells, but the underlying molecular mechanisms and functional relevance of this process remain unclear. We generated mice with Treg-specific IL-10Ra deficiency and subjected these mice to nephrotoxic serum-induced nephritis as a model of crescentic GN.

T-Bet Enhances Regulatory T Cell Fitness and Directs Control of Th1 Responses in Crescentic GN.

Th1 cells are central pathogenic mediators of crescentic GN (cGN). Mechanisms responsible for Th1 cell downregulation, however, remain widely unknown. Recently, it was proposed that activation of the Th1-characteristic transcription factor T-bet optimizes Foxp3 regulatory T (Treg) cells to counteract Th1-type inflammation.

IL-17F Promotes Tissue Injury in Autoimmune Kidney Diseases.

The T17 immune response has a central role in the pathogenesis of autoimmune diseases, implicating the T17 master cytokine, IL-17A, as the critical mediator of diseases such as human and experimental crescentic GN. However, the relative importance of additional T17 effector cytokines, including IL-17F, in immune-mediated tissue injury remains to be fully elucidated. Here, using a mouse model of acute crescentic GN (nephrotoxic nephritis), we identified CD4 T cells and γδ T cells as the major cellular source of IL-17F in the inflamed kidney.

Treg17 cells are programmed by Stat3 to suppress Th17 responses in systemic lupus.

Systemic lupus erythematosus (SLE) is a complex and potentially fatal autoimmune disorder. Although Th17 cells are thought to be central mediators of SLE, mechanisms underlying their counter regulation remain largely unknown. To help define this, we studied the function of the newly defined Stat3-dependent Th17-specific regulatory T cells (Treg17).

RORγt(+)Foxp3(+) Cells are an Independent Bifunctional Regulatory T Cell Lineage and Mediate Crescentic GN.

Cells expressing both the regulatory T cell (Treg)-inducing transcription factor Foxp3 and the Th17 transcription factor RORγt have been identified (biTregs). It is unclear whether RORγt(+)Foxp3(+) biTregs belong to the Th17-specific Treg17 cells, represent intermediates during Treg/Th17 transdifferentiation, or constitute a distinct cell lineage. Because the role of biTregs in inflammatory renal disease is also unknown, we studied these cells in the nephrotoxic nephritis (NTN) model of acute crescentic GN.

Inflammation-Induced IL-6 Functions as a Natural Brake on Macrophages and Limits GN.

IL-6 can mediate proinflammatory effects, and IL-6 receptor (IL-6R) blockade as a treatment for inflammatory diseases has entered clinical practice. However, opposing effects of IL-6 have been observed in models of GN. Although IL-6 is proinflammatory in murine lupus nephritis, protective effects have been observed for IL-6 in the nephrotoxic nephritis (NTN) model of acute crescentic GN.

Stat3 programs Th17-specific regulatory T cells to control GN.

A pathogenic role for Th17 cells in inflammatory renal disease is well established. The mechanisms underlying their counter-regulation are, however, largely unknown. Recently, Th17 lineage-specific regulatory T cells (Treg17) that depend on activation of the transcription factor Stat3 were identified.

B-cell-derived IL-10 does not vitally contribute to the clinical course of glomerulonephritis.

IL-10-secreting regulatory B cells have been postulated as negative mediators of inflammation. However, their impact on immune-mediated diseases requires further investigation. We recently found that IL-10-secreting B cells infiltrate the kidney during crescentic glomerulonephritis (GN).

Leukocyte-derived MMP9 is crucial for the recruitment of proinflammatory macrophages in experimental glomerulonephritis.

Matrix metalloproteinase 9 (MMP9) is a conditionally expressed enzyme and is upregulated in glomerulonephritis. Its function in these diseases, however, remains to be fully elucidated. The induction of nephrotoxic serum nephritis (NTN) in wild-type mice resulted in an upregulation of MMP9, followed by leukocyte infiltration, albuminuria, and subsequent renal failure.