title: 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.
authors.affiliation: III Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Paust
authors.forename: Jan-Eric
authors.initials: JE
authors.lastname: Turner
authors.forename: Jan-Hendrik
authors.initials: JH
authors.lastname: Riedel
authors.forename: Erik
authors.initials: E
authors.lastname: Disteldorf
authors.forename: Anett
authors.initials: A
authors.lastname: Peters
authors.forename: Tilman
authors.initials: T
authors.lastname: Schmidt
authors.forename: Christian
authors.initials: C
authors.lastname: Krebs
authors.forename: Joachim
authors.initials: J
authors.lastname: Velden
authors.forename: Hans-Willi
authors.initials: HW
authors.lastname: Mittrücker
authors.forename: Oliver M
authors.initials: OM
authors.lastname: Steinmetz
authors.forename: Rolf A K
authors.initials: RA
authors.lastname: Stahl
authors.forename: Ulf
authors.initials: U
authors.lastname: Panzer
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D057134:Antibodies, Neutralizing; D002450:Cell Communication; D002478:Cells, Cultured; D054418:Chemokine CCL20 / Q000378:metabolism; D054370:Chemokine CXCL9 / Q000378:metabolism; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte; D004195:Disease Models, Animal; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D005921:Glomerulonephritis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007074:Immunoglobulin G; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics; D020381:Interleukin-17 / Q000172:deficiency / Q000235:genetics; D007668:Kidney / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054399:Receptors, CCR6 / Q000172:deficiency / Q000235:genetics; D054367:Receptors, CXCR3 / Q000172:deficiency / Q000235:genetics; D012756:Sheep; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D013997:Time Factors
chemical_list: D057134:Antibodies, Neutralizing; C493447:CCL20 protein, mouse; C498126:CCR6 protein, mouse; D054418:Chemokine CCL20; D054370:Chemokine CXCL9; D018925:Chemokines; C485969:Cxcl9 protein, mouse; C515188:Cxcr3 protein, mouse; D018398:Homeodomain Proteins; D007074:Immunoglobulin G; D020381:Interleukin-17; D054399:Receptors, CCR6; D054367:Receptors, CXCR3; C064658:RAG-1 protein; D007371:Interferon-gamma