Chemokines play a critical role in the cross-regulation of Th1 and Th17 immune responses in murine crescentic glomerulonephritis

Abstract

Th1 and Th17 subtype effector CD4(+) T cells are thought to play a critical role in the pathogenesis of human and experimental crescentic glomerulonephritis. The time course, mechanism, and functions of Th1 and Th17 cell recruitment, and their potential interaction in glomerulonephritis, however, remain to be elucidated. We performed interventional studies using IL-17- and IFN-γ-gene-deficient mice, as well as neutralizing antibodies that demonstrated the importance of the Th17-mediated immune response during the early phase of the disease. At a later stage, we found that Th1 cells were critical mediators of renal tissue injury. Early recruitment of IL-17-producing Th17 cells triggered expression of the chemokine CXCL9 in the kidney that drove the infiltration of Th1 cells bearing its receptor CXCR3. At a later stage, Th1 cell-derived IFN-γ was found to inhibit local chemokine CCL20 expression, acting through its receptor CCR6 on Th17 cells, thereby limiting the renal Th17 immune response. Thus, our findings provide mechanistic evidence for a cytokine-chemokine-driven feedback loop that orchestrates the observed differential Th1 and Th17 cell infiltration into the inflamed kidney. This contributes to the observed time-dependent function of these two major pathogenic effector CD4(+) T cell subsets in crescentic glomerulonephritis.

Glomerulopathy Induced by Immunization with a Peptide Derived from the Goodpasture Antigen α3IV-NC1

“…Indeed, T cell transfers in WKY rats or in HLA-DRB1*15:01 transgenic mice have also suggested a direct participation of T cells in the emergence of crescentic GN (20,21). Our results also support studies in the EAG and the nephrotoxic nephritis model, which suggest a role of both Th1 and Th17 cells in the development of crescentic GN (15,(20)(21)(22)(23)(24)(25).…”

Regulatory T Cell–Derived IL-10 Ameliorates Crescentic GN

“…Glomerular deposition of sheep IgG, mouse IgG, and C3 was scored from 0 to 3 in 30 glomeruli per mouse as previously described. 38 …”

CXCR3+ Regulatory T Cells Control TH1 Responses in Crescentic GN

“…As a consequence, we performed all functional Treg analyses at day 30, which is also a time point of a strong renal T H 1 response in this GN model. 12 Next, we examined the chemokine receptor profile of renal Tregs in the course of experimental GN by flow cytometry. Of the tested chemokine receptors, CXCR3 was predominantly expressed on Tregs at day 30 (approximately 52%) followed by CCR4 (approximately 26%), CCR5 (approximately 14%), CCR6 (approximately 14%), and CCR7 (approximately 8%) ( Figure 2E).…”

“…9,10 Studies in patients with crescentic GN and experimental models of GN have shown the importance of CD4 + T cell-driven immune responses in this disease group. 9 Today, there is clear evidence that the recruitment of T H 1 11,12 and T H 17 [13][14][15] cells into the inflamed kidney drives renal tissue damage, whereas Tregs suppress overwhelming immune responses. [16][17][18] In this study, we investigated the functional role of chemokine receptors expressed on Tregs in crescentic GN.…”