Neutrophil trafficking to sites of inflammation is essential for the defense against bacterial and fungal infections, but also contributes to tissue damage in TH17-mediated autoimmunity. This process is regulated by chemokines, which often show an overlapping expression pattern and function in pathogen- and autoimmune-induced inflammatory reactions. Using a murine model of crescentic GN, we show that the pathogenic TH17/IL-17 immune response induces chemokine (C-X-C motif) ligand 5 (CXCL5) expression in kidney tubular cells, which recruits destructive neutrophils that contribute to renal tissue injury. By contrast, CXCL5 was dispensable for neutrophil recruitment and effective bacterial clearance in a murine model of acute bacterial pyelonephritis. In line with these findings, CXCL5 expression was highly upregulated in the kidneys of patients with ANCA-associated crescentic GN as opposed to patients with acute bacterial pyelonephritis. Our data therefore identify CXCL5 as a potential therapeutic target for the restriction of pathogenic neutrophil infiltration in TH17-mediated autoimmune diseases while leaving intact the neutrophil function in protective immunity against invading pathogens.

The Th17 immune response appears to contribute to the pathogenesis of human and experimental crescentic GN, but the cell types that produce IL-17A in the kidney, the mechanisms involved in its induction, and the IL-17A–mediated effector functions that promote renal tissue injury are incompletely understood. Here, using a murine model of crescentic GN, we found that CD4⁺ T cells, γδ T cells, and a population of CD3⁺CD4⁻CD8⁻γδT cell receptor⁻NK1.1⁻ T cells all produce IL-17A in the kidney. A time course analysis identified γδ T cells as a major source of IL-17A in the early phase of disease, before the first CD4⁺ Th17 cells arrived. The production of IL-17A by renal γδ T cells depended on IL-23p19 signaling and retinoic acid–related orphan receptor-γt but not on IL-1β or IL-6. In addition, depletion of dendritic cells, which produce IL-23 in the kidney, reduced IL-17A production by renal γδ T cells. Furthermore, the lack of IL-17A production in γδ T cells, as well as the absence of all γδ T cells, reduced neutrophil recruitment into the kidney and ameliorated renal injury. Taken together, these data suggest that γδ T cells produce IL-17A in the kidney, induced by IL-23, promoting neutrophil recruitment, and contributing to the immunopathogenesis of crescentic GN.

Objective: The CD4+ T cell immune response plays a pivotal role in the immunopathogenesis of human and experimental lupus nephritis, but the contribution of the Th17/interleukin‐17 (IL‐17) immune pathway to renal tissue injury in systemic lupus erythematosus (SLE) remains to be elucidated. The aim of this study was to characterize the function of the Th17/IL‐17A immune response in 2 murine models of lupus nephritis.Methods: IL‐17A–deficient MRL/MPJ‐Fas^lpr/2J (MRL/lpr) mice were generated, and the clinical course of nephritis was monitored by assessing the levels of albuminuria, extent of renal tissue injury, and functional parameters. In addition, lupus‐prone (NZB × NZW)F1 (NZB/NZW) mice were treated with anti–IL‐17A and anti–interferon‐γ (anti‐IFNγ) antibodies, and their effects on the clinical course of lupus nephritis were assessed.Results: Characterization of renal IL‐17A–producing and IFNγ‐producing T cells in MRL/lpr and NZB/NZW mice revealed low numbers of infiltrating CD3+IL‐17A+ cells. Renal IL‐17A was mainly produced by CD4/CD8 double‐negative CD3+ T cells and CD4+ Th17 cells. In contrast, the number of renal CD3+IFNγ+ cells continuously increased over time and largely consisted of typical CD4+ Th1 cells. IL‐17A deficiency did not affect the morphologic or functional parameters in MRL/lpr mice with lupus nephritis, nor did IL‐17A neutralization affect the clinical course of nephritis in NZB/NZW mice, but anti‐IFNγ treatment attenuated the severity of the disease.Conclusion: The Th17/IL‐17A immune response plays no major role in the immunopathogenesis of lupus nephritis in MRL/lpr and NZB/NZW mice. Thus, the results of this study do not support the hypothesis that IL‐17A targeting could be an intriguing new therapeutic approach for the management of proliferative lupus nephritis in SLE patients.

Chemokines and chemokine receptors are implicated in regulatory T cell (Treg) trafficking to sites of inflammation and suppression of excessive immune responses in inflammatory and autoimmune diseases; however, the specific requirements for Treg migration into the inflamed organs and the positioning of these cells within the tissue are incompletely understood. Here, we report that Tregs expressing the T_H1–associated chemokine receptor CXCR3 are enriched in the kidneys of patients with ANCA–associated crescentic GN and colocalize with CXCR3⁺ effector T cells. To investigate the functional role of CXCR3⁺ Tregs, we generated mice that lack CXCR3 in Tregs specifically (Foxp3^eGFP-Cre × Cxcr3^fl/fl) and induced experimental crescentic GN. Treg-specific deletion of CXCR3 resulted in reduced Treg recruitment to the kidney and an overwhelming T_H1 immune response, with an aggravated course of the nephritis that was reversible on anti-IFNγ treatment. Together, these findings show that a subset of Tregs expresses CXCR3 and thereby, acquires trafficking properties of pathogenic CXCR3⁺ T_H1 cells, allowing Treg localization and control of excessive T_H1 responses at sites of inflammation.

Natural killer T-cells are a subset of innate-like T-cells with the ability to bridge innate and adaptive immunity. There is great interest in harnessing these cells to improve tumor therapy; however, greater understanding of invariant NKT (iNKT) cell biology is needed. The first step is to learn more about NKT development within the thymus. Recent studies suggest lineage separation of murine iNKT cells into iNKT1, iNKT2, and iNKT17 cells instead of shared developmental stages. This review will focus on these new studies and will discuss the evidence for lineage separation in contrast to shared developmental stages. The author will also highlight the classifications of murine iNKT cells according to identified transcription factors and cytokine production, and will discuss transcriptional and posttranscriptional regulations, and the role of mammalian target of rapamycin. Finally, the importance of these findings for human cancer therapy will be briefly discussed.

CD4⁺ T cells play a pivotal role in the pathogenesis of autoimmune disease, including human and experimental crescentic GN. Micro-RNAs (miRs) have emerged as important regulators of immune cell development, but the impact of miRs on the regulation of the CD4⁺ T cell immune response remains to be fully clarified. Here, we report that miR-155 expression is upregulated in the kidneys of patients with ANCA-associated crescentic GN and a murine model of crescentic GN (nephrotoxic nephritis). To elucidate the potential role of miR-155 in T cell-mediated inflammation, nephritis was induced in miR-155^−/− and wild-type mice. The systemic and renal nephritogenic T_H17 immune response decreased markedly in nephritic miR-155^−/− mice. Consistent with this finding, miR-155–deficient mice developed less severe nephritis, with reduced histologic and functional injury. Adoptive transfer of miR-155^−/− and wild-type CD4⁺ T cells into nephritic recombination activating gene 1-deficient (Rag-1^−/−) mice showed the T cell-intrinsic importance of miR-155 for the stability of pathogenic T_H17 immunity. These findings indicate that miR-155 drives the T_H17 immune response and tissue injury in experimental crescentic GN and show that miR-155 is a potential therapeutic target in T_H17-mediated diseases.