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T helper type 17 cells in immune-mediated glomerular disease

Nature Reviews Nephrology volume 13, pages 647–659 (2017)Cite this article

Subjects

Key Points

  • The IL-17/T helper type 17 (TH17) axis is a key mediator of renal tissue injury in models of renal immune-mediated disease

  • In patients with autoimmune kidney diseases, such as anti-neutrophil cytoplasmic antibody-associated glomerulonephritis or lupus nephritis, IL-17 serum levels correlate with disease activity; moreover, TH17 cells are abundant in kidneys of these patients

  • In experimental crescentic glomerulonephritis, intestinal TH17 cells can migrate into the kidney where they contribute to renal pathology

  • TH17 cells in the gut are induced by intestinal microbiota; microbial depletion with antibiotics reduces the renal TH17 response and tissue injury in experimental crescentic glomerulonephritis

  • IL-17 and IL-23-specific antibody treatment are remarkably effective in psoriasis, but their role in immune-mediated kidney disease has not been studied

Abstract

CD4+ T cells are important drivers of tissue damage in immune-mediated renal diseases, such as anti-glomerular basement membrane glomerulonephritis, anti-neutrophil cytoplasmic antibody-associated glomerulonephritis, and lupus nephritis. The discovery of a distinct, IL-17-producing CD4+ T-cell lineage termed T helper type 17 (TH17) cells has markedly advanced current understanding of the pathogenic mechanisms of organ-specific immunity and the pathways that lead to target organ damage. TH17 cells are characterized by the expression of the transcription factor RORγt, the production of the pro-inflammatory cytokines IL-17A, IL-17F, IL-22, and high expression of the chemokine receptor C-C-motif chemokine receptor 6 (CCR6). An emerging body of evidence from experimental models and human studies supports a key role for these cells in the development of renal damage, and has led to the identification of targets to inhibit the production of TH17 cells in the intestine, their migration, or their actions within the kidney. Here, we describe the identification, regulation, and function of TH17 cells and their associated pathways in immune-mediated kidney diseases, with a particular focus on the mechanisms underlying renal tissue injury. We also discuss the rationale for the translation of these findings into new therapeutic approaches in patients with autoimmune kidney disease.

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Figure 1: Differentiation of naive T cells into T helper type 17 (TH17) cells.
Figure 2: Potential mechanisms of T helper type 17 (TH17) cell-driven tissue injury in glomerulonephritis.
Figure 3: IL-17 signalling pathways.
Figure 4: The fate of renal IL-17-producing cells in glomerulonephritis.
Figure 5: Relationship between intestinal microbiota and kidney infiltrating T helper type 17 (TH17) cells.
Figure 6: Potential therapeutic targets of the TH17 immune response in the kidney.

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Acknowledgements

We apologize to all colleagues whose work could not be cited or discussed in greater detail due to space restrictions. Our work described in this Review was supported by grants from the Deutsche Forschungsgemeinschaft (SFB 1192: to C.F.K. and U.P.), and grants from the Deutsche Nierenstiftung and Deutsche Gesellschaft für Nephrologie to C.F.K. We thank Oliver M. Steinmetz and Jan-Eric Turner, Universitätsklinikum Hamburg-Eppendorf, for critical reading of the manuscript before submission.

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  1. III. Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Martinistrasse 52, Hamburg, 20246, Germany

    Christian F. Krebs, Tilman Schmidt, Jan-Hendrik Riedel & Ulf Panzer

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  1. Christian F. Krebs
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  2. Tilman Schmidt
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All authors contributed equally to researching data for the article, discussion of the content, and writing the article. C.F.K. and U.P. revised and/or edited the manuscript before submission.

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Correspondence to Christian F. Krebs or Ulf Panzer.

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PowerPoint slides

Glossary

T regulatory (Treg) cells

An immunosuppressive T-cell subset that controls the inflammatory reaction. Distinct subsets of Treg cells have been identified (for example, Foxp3+ Treg cells and FoxP3−IL-10+ type 1 Treg (TR1) cells)

T follicular helper (TFH) cells

A subset of CD4+ T cells that facilitate B-cell activation in the germinal centre and the differentiation of long-lived plasma cells

Delayed type hypersensitivity

(DTH). DTH or type IV hypersensitivity is a form of T cell-mediated immune reaction that is triggered by antigen in the skin and appears hours to days after antigen challenge.

γδ T cells

A subset of T cells that develop in the thymus and express a γδ heterodimeric T-cell receptor. These cells have more innate-like functions than do conventional αβ T cells.

Peyer's patches

A structure localized in the intestinal wall that consists of organized lymphoid follicles. As a part of the gut associated lymphoid tissue (GALT) they contribute to homeostasis at sites of food-derived antigens and microbiota.

Nanobody

A single-domain antibody derived from camelid heavy chain antibodies that is 10-fold smaller than conventional antibodies.

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Krebs, C., Schmidt, T., Riedel, JH. et al. T helper type 17 cells in immune-mediated glomerular disease. Nat Rev Nephrol 13, 647–659 (2017). https://doi.org/10.1038/nrneph.2017.112

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