Autoimmune Renal Disease Is Exacerbated by S1P-Receptor-1-Dependent Intestinal Th17 Cell Migration to the Kidney.

Th17 cells are most abundant in the gut, where their presence depends on the intestinal microbiota. Here, we examined whether intestinal Th17 cells contribute to extra-intestinal Th17 responses in autoimmune kidney disease. We found high frequencies of Th17 cells in the kidneys of patients with antineutrophil cytoplasmatic antibody (ANCA)-associated glomerulonephritis. We utilized photoconversion of intestinal cells in Kaede mice to track intestinal T cell mobilization upon glomerulonephritis induction, and we found that Th17 cells egress from the gut in a S1P-receptor-1-dependent fashion and subsequently migrate to the kidney via the CCL20/CCR6 axis. Depletion of intestinal Th17 cells in germ-free and antibiotic-treated mice ameliorated renal disease, whereas expansion of these cells upon Citrobacter rodentium infection exacerbated pathology. Thus, in some autoimmune settings, intestinal Th17 cells migrate into target organs, where they contribute to pathology. Targeting the intestinal Th17 cell "reservoir" may present a therapeutic strategy for these autoimmune disorders.

Upregulation of HLA-F expression by BK polyomavirus infection induces immune recognition by KIR3DS1-positive natural killer cells.

BK polyomavirus-associated nephropathy is a common complication after kidney transplantation leading to reduced graft function or loss. The molecular pathogenesis of BK polyomavirus-induced nephropathy is not well understood. A recent study had described a protective effect of the activating natural killer cell receptor KIR3DS1 in BK polyomavirus-associated nephropathy, suggesting a role of NK cells in modulating disease progression. Using an in vitro cell culture model of human BK polyomavirus infection and kidney biopsy samples from patients with BK polyomavirus-associated nephropathy, we observed significantly increased surface expression of the ligand for KIR3DS1, HLA-F, on BK polyomavirus-infected kidney tubular cells. Upregulation of HLA-F expression resulted in significantly increased binding of KIR3DS1 to BK polyomavirus-infected cells and activation of primary KIR3DS-positive natural killer cells. Thus, our data provide a mechanism by which KIR3DS-positive natural killer cells can control BK polyomavirus infection of the kidney, and rationale for exploring HLA-F/KIR3DS1 interactions for immunotherapeutic approaches in BK polyomavirus-associated nephropathy.

Plasticity of Th17 Cells in Autoimmune Kidney Diseases.

The ability of CD4(+) T cells to differentiate into pathogenic Th1 and Th17 or protective T regulatory cells plays a pivotal role in the pathogenesis of autoimmune diseases. Recent data suggest that CD4(+) T cell subsets display a considerable plasticity. This plasticity seems to be a critical factor for their pathogenicity, but also for the potential transition of pathogenic effector T cells toward a more tolerogenic phenotype. The aim of the current study was to analyze the plasticity of Th17 cells in a mouse model of acute crescentic glomerulonephritis and in a mouse chronic model of lupus nephritis. By transferring in vitro generated, highly purified Th17 cells and by using IL-17A fate reporter mice, we demonstrate that Th17 cells fail to acquire substantial expression of the Th1 and Th2 signature cytokines IFN-γ and IL-13, respectively, or the T regulatory transcription factor Foxp3 throughout the course of renal inflammation. In an attempt to therapeutically break the stability of the Th17 phenotype in acute glomerulonephritis, we subjected nephritic mice to CD3-specific Ab treatment. Indeed, this treatment induced an immunoregulatory phenotype in Th17 cells, which was marked by high expression of IL-10 and attenuated renal tissue damage in acute glomerulonephritis. In summary, we show that Th17 cells display a minimum of plasticity in acute and chronic experimental glomerulonephritis and introduce anti-CD3 treatment as a tool to induce a regulatory phenotype in Th17 cells in the kidney that may be therapeutically exploited.

KIR3DS1 directs NK cell-mediated protection against human adenovirus infections.

Human adenoviruses (HAdVs) are a major cause for disease in children, in particular after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Currently, effective therapies for HAdV infections in immunocompromised hosts are lacking. To decipher immune recognition of HAdV infection and determine new targets for immune-mediated control, we used an HAdV infection 3D organoid system, based on primary human intestinal epithelial cells. HLA-F, the functional ligand for the activating NK cell receptor KIR3DS1, was strongly up-regulated and enabled enhanced killing of HAdV5-infected cells in organoids by KIR3DS1+ NK cells. In contrast, HLA-A and HLA-B were significantly down-regulated in HAdV5-infected organoids in response to adenoviral E3/glycoprotein19K, consistent with evasion from CD8+ T cells. Immunogenetic analyses in a pediatric allo-HSCT cohort showed a reduced risk to develop severe HAdV disease and faster clearance of HAdV viremia in children receiving KIR3DS1+/HLA-Bw4+ donor cells compared with children receiving non­KIR3DS1+/HLA-Bw4+ cells. These findings identify the KIR3DS1/HLA-F axis as a new target for immunotherapeutic strategies against severe HAdV disease.

Function of the Th17/interleukin-17A immune response in murine lupus nephritis.

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.