title: The Mechanisms of Human Renal Epithelial Cell Modulation of Autologous Dendritic Cell Phenotype and Function.
abstract: Proximal tubule epithelial cells (PTEC) of the kidney line the proximal tubule downstream of the glomerulus and play a major role in the re-absorption of small molecular weight proteins that may pass through the glomerular filtration process. In the perturbed disease state PTEC also contribute to the inflammatory disease process via both positive and negative mechanisms via the production of inflammatory cytokines which chemo-attract leukocytes and the subsequent down-modulation of these cells to prevent uncontrolled inflammatory responses. It is well established that dendritic cells are responsible for the initiation and direction of adaptive immune responses. Both resident and infiltrating dendritic cells are localised within the tubulointerstitium of the renal cortex, in close apposition to PTEC, in inflammatory disease states. We previously demonstrated that inflammatory PTEC are able to modulate autologous human dendritic cell phenotype and functional responses. Here we extend these findings to characterise the mechanisms of this PTEC immune-modulation using primary human PTEC and autologous monocyte-derived dendritic cells (MoDC) as the model system. We demonstrate that PTEC express three inhibitory molecules: (i) cell surface PD-L1 that induces MoDC expression of PD-L1; (ii) intracellular IDO that maintains the expression of MoDC CD14, drives the expression of CD80, PD-L1 and IL-10 by MoDC and inhibits T cell stimulatory capacity; and (iii) soluble HLA-G (sHLA-G) that inhibits HLA-DR and induces IL-10 expression by MoDC. Collectively the results demonstrate that primary human PTEC are able to modulate autologous DC phenotype and function via multiple complex pathways. Further dissection of these pathways is essential to target therapeutic strategies in the treatment of inflammatory kidney disorders.
authors.affiliation: Conjoint Kidney Research Laboratory, Pathology Queensland, Brisbane, Queensland, Australia; Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Sampangi
authors.affiliation: Conjoint Kidney Research Laboratory, Pathology Queensland, Brisbane, Queensland, Australia; Department of Renal Medicine, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Kassianos
authors.affiliation: Conjoint Kidney Research Laboratory, Pathology Queensland, Brisbane, Queensland, Australia; Department of Renal Medicine, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
authors.forename: Xiangju
authors.initials: X
authors.lastname: Wang
authors.affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Beagley
authors.affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.
authors.forename: Travis
authors.initials: T
authors.lastname: Klein
authors.affiliation: Conjoint Kidney Research Laboratory, Pathology Queensland, Brisbane, Queensland, Australia; Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.
authors.forename: Sadia
authors.initials: S
authors.lastname: Afrin
authors.affiliation: Conjoint Kidney Research Laboratory, Pathology Queensland, Brisbane, Queensland, Australia; Department of Renal Medicine, 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; Department of Renal Medicine, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia; Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia; Medical School, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Ray
authors.initials: R
authors.lastname: Wilkinson
mesh_terms: D015703:Antigens, CD / Q000276:immunology; D060890:B7-H1 Antigen / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D005434:Flow Cytometry; D006684:HLA-DR Antigens / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping; D016753:Interleukin-10 / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000166:cytology* / Q000276:immunology
chemical_list: D015703:Antigens, CD; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D006684:HLA-DR Antigens; D016753:Interleukin-10