Egress of intestinal T_H17 cells in autoimmune renal disease

Credit: Lara Crow/NPG

Studies over the past few years have revealed a role for type 17 T helper (T_H17) cells in the pathogenesis of several autoimmune diseases, including crescentic glomerulonephritis. These cells are most abundant in the lamina propria of the small intestine under homeostatic conditions; however, they have been observed in kidneys of murine models of crescentic glomerulonephritis where they produce cytokines such as IL-17A, which contribute to renal injury and neutrophil recruitment. Although progress has been made in understanding the effector functions of T_H17 cells in target organs, the origin of these cells remains unclear. New findings demonstrate that T_H17 cells egress from the gut to the kidney in a manner that is dependent on S1P-receptor 1 and CCL20/CCR6 signalling and that depletion of intestinal T_H17 cells ameliorates renal disease. “This finding is of functional relevance, since the absence of intestinal T_H17 cells in germ-free mice and their depletion in mice treated with antibiotics reduces the renal T_H17 response and tissue injury in our model of glomerulonephritis,” explains researcher Ulf Panzer. “Oral application of vancomycin is sufficient to reduce the number of intestinal T_H17 cells, as well as T_H17 responses in the kidney, leading to an ameliorated course of crescentic glomerulonephritis without any significant adverse effects, highlighting the great potential of this novel treatment strategy.”

We directly demonstrate that T_H17 cells from the intestine migrate into the kidney and drive renal tissue injury

To assess the relationship between microbiota-induced T_H17 cells in the gut and extra-intestinal T_H17 responses in the kidney, Panzer and colleagues first characterized the composition of T-cell subsets in renal biopsy samples from patients with antineutrophil cytoplasmic antibody-associated glomerulonephritis and in mice with experimental nephrotoxic nephritis. “Due to technical limitations, analysis of T_H17 cells in the kidney of patients with glomerulonephritis was not previously possible, but using flow cytometry we identified high frequencies of T_H17 cells in human and mouse crescentic glomerulonephritis,” says Panzer. The researchers next performed transfer experiments of renal and intestinal T_H17 cells from Il17a-reporter mice into immunodeficient mice to determine the nephritogenic potential of intestinal-derived T_H17 cells in experimental crescentic glomerulonephritis. T_H17 cells from the kidney of nephritic Il17a-reporter mice migrated preferentially to the intestine of host mice whereas T_H17 cells from the small intestine of Il17a-reporter mice migrated to the kidney of host mice following the induction of nephrotoxic nephritis. To track the migration of intestinal T cells following the induction of glomerulonephritis, the researchers used mice engineered to ubiquitously express Kaede, a photoconvertible protein that changes its fluorescence emission upon photoactivation. “Before our study, only indirect evidence for the involvement of intestinal T_H17 cells in autoimmune diseases was available, but using Kaede-transgenic mice, we directly demonstrate that T_H17 cells from the intestine migrate into the kidney and drive renal tissue injury in crescentic glomerulonephritis,” explains Panzer. “We also show that T_H17 cells migrate from the small intestine in a S1P receptor 1-dependent fashion and subsequently migrate into the inflamed kidney via the CCL20/CCR6 axis.”

Finally, the researchers demonstrate that depletion of intestinal T_H17 cells in germ-free or antibiotic-treated mice ameliorated renal disease whereas activation of T_H17 cells with Citrobacter rodentium led to a more severe renal phenotype. “Our findings have important implications for the mechanistic understanding of how the reservoir of microbiota-induced intestinal T_H17 cells contributes to organ-specific autoimmune disease and for the development of novel treatment strategies in T_H17-driven autoimmune disorders,” says Panzer. “Targeting this intestinal T_H17 cell reservoir might present a therapeutic strategy for autoimmune disorders such as crescentic glomerulonephritis.”