title: Interferon-γ production by tubulointerstitial human CD56brightnatural killer cells contributes to renal fibrosis and chronic kidney disease progression.
abstract: Natural killer (NK) cells are a population of lymphoid cells that play a significant role in mediating innate immune responses. Studies in mice suggest a pathological role for NK cells in models of kidney disease. In this study, we characterized the NK cell subsets present in native kidneys of patients with tubulointerstitial fibrosis, the pathological hallmark of chronic kidney disease. Significantly higher numbers of total NK cells (CD3-CD56+) were detected in renal biopsies with tubulointerstitial fibrosis compared with diseased biopsies without fibrosis and healthy kidney tissue using multi-color flow cytometry. At a subset level, both the CD56dimNK cell subset and particularly the CD56brightNK cell subset were elevated in fibrotic kidney tissue. However, only CD56brightNK cells significantly correlated with the loss of kidney function. Expression of the tissue-retention and -activation molecule CD69 on CD56brightNK cells was significantly increased in fibrotic biopsy specimens compared with non-fibrotic kidney tissue, indicative of a pathogenic phenotype. Further flow cytometric phenotyping revealed selective co-expression of activating receptor CD335 (NKp46) and differentiation marker CD117 (c-kit) on CD56brightNK cells. Multi-color immunofluorescent staining of fibrotic kidney tissue localized the accumulation of NK cells within the tubulointerstitium, with CD56brightNK cells (NKp46+CD117+) identified as the source of pro-inflammatory cytokine interferon-γ within the NK cell compartment. Thus, activated interferon-γ-producing CD56brightNK cells are positioned to play a key role in the fibrotic process and progression to chronic kidney disease.
authors.affiliation: Conjoint Kidney Research Laboratory, Pathology Queensland, Brisbane, Queensland, Australia; Kidney Health Service, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia; Institute of Health and Biomedical Innovation/School of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia.
authors.forename: Becker M P
authors.initials: BMP
authors.lastname: Law
authors.affiliation: Conjoint Kidney Research Laboratory, Pathology Queensland, Brisbane, Queensland, Australia; Kidney Health Service, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia; Institute of Health and Biomedical Innovation/School of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia; University of Queensland Medical School, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Ray
authors.initials: R
authors.lastname: Wilkinson
authors.affiliation: Conjoint Kidney Research Laboratory, Pathology Queensland, Brisbane, Queensland, Australia; Kidney Health Service, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
authors.forename: Xiangju
authors.initials: X
authors.lastname: Wang
authors.affiliation: Conjoint Kidney Research Laboratory, Pathology Queensland, Brisbane, Queensland, Australia; Kidney Health Service, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
authors.forename: Katrina
authors.initials: K
authors.lastname: Kildey
authors.affiliation: Conjoint Kidney Research Laboratory, Pathology Queensland, Brisbane, Queensland, Australia; Kidney Health Service, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
authors.forename: Mae
authors.initials: M
authors.lastname: Lindner
authors.affiliation: Conjoint Kidney Research Laboratory, Pathology Queensland, Brisbane, Queensland, Australia; Kidney Health Service, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Rist
authors.affiliation: Institute of Health and Biomedical Innovation/School of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Beagley
authors.affiliation: Conjoint Kidney Research Laboratory, Pathology Queensland, Brisbane, Queensland, Australia; Kidney Health Service, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
authors.forename: Helen
authors.initials: H
authors.lastname: Healy
authors.affiliation: Conjoint Kidney Research Laboratory, Pathology Queensland, Brisbane, Queensland, Australia; Kidney Health Service, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia; Institute of Health and Biomedical Innovation/School of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia; University of Queensland Medical School, University of Queensland, Brisbane, Queensland, Australia. Electronic address: andrew.kassianos@qimrberghofer.edu.au.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Kassianos
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000032:analysis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D001706:Biopsy; D019002:CD56 Antigen / Q000032:analysis*; D016022:Case-Control Studies; D018450:Disease Progression; D005260:Female; D005355:Fibrosis; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007371:Interferon-gamma / Q000032:analysis*; D007684:Kidney Tubules / Q000276:immunology* / Q000473:pathology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000473:pathology; D037181:Lectins, C-Type / Q000032:analysis; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000032:analysis; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis; D051436:Renal Insufficiency, Chronic / Q000276:immunology* / Q000473:pathology; D015398:Signal Transduction; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D019002:CD56 Antigen; D007371:Interferon-gamma; D037181:Lectins, C-Type; D055627:Natural Cytotoxicity Triggering Receptor 1; D019009:Proto-Oncogene Proteins c-kit; D000099192:CD69 Antigens; C573415:IFNG protein, human; C522918:NCAM1 protein, human; C112260:NCR1 protein, human
keywords: chronic kidney disease; human natural killer cells; interferon-γ; interstitial fibrosis; tubulointerstitium