title: Glomerular common gamma chain confers B- and T-cell-independent protection against glomerulonephritis.
abstract: Crescentic glomerulonephritis is a life-threatening renal disease that has been extensively studied by the experimental anti-glomerular basement membrane glomerulonephritis (anti-GBM-GN) model. Although T cells have a significant role in this model, athymic/nude mice and rats still develop severe renal disease. Here we further explored the contribution of intrinsic renal cells in the development of T-cell-independent GN lesions. Anti-GBM-GN was induced in three strains of immune-deficient mice (Rag2-/-, Rag2-/-Il2rg-/-, and Rag2-/-Il2rb-/-) that are devoid of either T/B cells or T/B/NK cells. The Rag2-/-Il2rg-/-or Rag2-/-Il2rb-/-mice harbor an additional deletion of either the common gamma chain (γC) or the interleukin-2 receptor β subunit (IL-2Rβ), respectively, impairing IL-15 signaling in particular. As expected, all these strains developed severe anti-GBM-GN. Additionally, bone marrow replenishment experiments allowed us to deduce a protective role for the glomerular-expressed γC during anti-GBM-GN. Given that IL-15 has been found highly expressed in nephritic kidneys despite the absence of lymphocytes, we then studied this cytokine in vitro on primary cultured podocytes from immune-deficient mice (Rag2-/-Il2rg-/-and Rag2-/-Il2rb-/-) compared to controls. IL-15 induced downstream activation of JAK1/3 and SYK in primary cultured podocytes. IL-15-dependent JAK/SYK induction was impaired in the absence of γC or IL-2Rβ. We found γC largely induced on podocytes during human glomerulonephritis. Thus, renal lesions are indeed modulated by intrinsic glomerular cells through the γC/IL-2Rβ receptor response, to date classically described only in immune cells.
authors.affiliation: Unité Mixte de Recherche (UMR) 1155, Institut National de la Santé et de la Recherche Médicale (Inserm), Paris, France; Sorbonne Universités, Université Pierre et Marie Curie Paris 06, Paris, France; Urgences Néphrologiques et Transplantation Rénale, Hôpital Tenon, Assistance Publique - Hôpitaux de Paris, Paris, France.
authors.forename: Yosu
authors.initials: Y
authors.lastname: Luque
authors.affiliation: Unité Mixte de Recherche (UMR) 1155, Institut National de la Santé et de la Recherche Médicale (Inserm), Paris, France; Sorbonne Universités, Université Pierre et Marie Curie Paris 06, Paris, France; Plateforme d'imagerie et de cytométrie de l'hôpital Tenon, Unité Mixte de Recherche (UMR) 1155, Institut National de la Santé et de la Recherche Médicale (Inserm), Paris, France; Sorbonne Universités, Université Pierre et Marie Curie Paris 06, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Cathelin
authors.affiliation: Unité Mixte de Recherche (UMR) 1155, Institut National de la Santé et de la Recherche Médicale (Inserm), Paris, France; Sorbonne Universités, Université Pierre et Marie Curie Paris 06, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Vandermeersch
authors.affiliation: Unité Mixte de Recherche (UMR) 1155, Institut National de la Santé et de la Recherche Médicale (Inserm), Paris, France; Sorbonne Universités, Université Pierre et Marie Curie Paris 06, Paris, France.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Xu
authors.affiliation: Unité Mixte de Recherche (UMR) 1155, Institut National de la Santé et de la Recherche Médicale (Inserm), Paris, France; Sorbonne Universités, Université Pierre et Marie Curie Paris 06, Paris, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Sohier
authors.affiliation: Unité Mixte de Recherche (UMR) 1155, Institut National de la Santé et de la Recherche Médicale (Inserm), Paris, France; Sorbonne Universités, Université Pierre et Marie Curie Paris 06, Paris, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Placier
authors.affiliation: Unité Mixte de Recherche (UMR) 1155, Institut National de la Santé et de la Recherche Médicale (Inserm), Paris, France; Urgences Néphrologiques et Transplantation Rénale, Hôpital Tenon, Assistance Publique - Hôpitaux de Paris, Paris, France.
authors.forename: Yi-Chun
authors.initials: YC
authors.lastname: Xu-Dubois
authors.affiliation: Urgences Néphrologiques et Transplantation Rénale, Hôpital Tenon, Assistance Publique - Hôpitaux de Paris, Paris, France.
authors.forename: Kevin
authors.initials: K
authors.lastname: Louis
authors.affiliation: Unité Mixte de Recherche (UMR) 1155, Institut National de la Santé et de la Recherche Médicale (Inserm), Paris, France; Sorbonne Universités, Université Pierre et Marie Curie Paris 06, Paris, France; Urgences Néphrologiques et Transplantation Rénale, Hôpital Tenon, Assistance Publique - Hôpitaux de Paris, Paris, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Hertig
authors.affiliation: Inserm, UMR 1126, Institut Universitaire d'Hématologie, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Bories
authors.affiliation: Inserm U1020, Université Paris Descartes, Paris, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Vasseur
authors.affiliation: Weill Cornell Medicine, The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, New York, New York, USA.
authors.forename: Fabien
authors.initials: F
authors.lastname: Campagne
authors.affiliation: Unité Immunité Innée, Institut Pasteur, Inserm U1223, Paris, France.
authors.forename: James P
authors.initials: JP
authors.lastname: Di Santo
authors.affiliation: Unité Immunité Innée, Institut Pasteur, Inserm U1223, Paris, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Vosshenrich
authors.affiliation: Unité Mixte de Recherche (UMR) 1155, Institut National de la Santé et de la Recherche Médicale (Inserm), Paris, France; Sorbonne Universités, Université Pierre et Marie Curie Paris 06, Paris, France; Urgences Néphrologiques et Transplantation Rénale, Hôpital Tenon, Assistance Publique - Hôpitaux de Paris, Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Rondeau
authors.affiliation: Unité Mixte de Recherche (UMR) 1155, Institut National de la Santé et de la Recherche Médicale (Inserm), Paris, France; Sorbonne Universités, Université Pierre et Marie Curie Paris 06, Paris, France; Urgences Néphrologiques et Transplantation Rénale, Hôpital Tenon, Assistance Publique - Hôpitaux de Paris, Paris, France; Weill Cornell Medicine, The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, New York, New York, USA. Electronic address: laurent.mesnard@aphp.fr.
authors.forename: Laurent
authors.initials: L
authors.lastname: Mesnard
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000633:toxicity; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D005921:Glomerulonephritis / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D019409:Interleukin-15 / Q000276:immunology / Q000378:metabolism; D053646:Interleukin-2 Receptor beta Subunit / Q000235:genetics / Q000276:immunology*; D053613:Janus Kinase 1 / Q000378:metabolism; D053616:Janus Kinase 3 / Q000378:metabolism; D007678:Kidney Glomerulus / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D007694:Killer Cells, Natural; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D050199:Podocytes / Q000276:immunology* / Q000378:metabolism; D061251:Primary Cell Culture; D015398:Signal Transduction; D000072377:Syk Kinase / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D004268:DNA-Binding Proteins; C508022:Il2rb protein, mouse; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; D019409:Interleukin-15; D053646:Interleukin-2 Receptor beta Subunit; C499308:Rag2 protein, mouse; C051951:antiglomerular basement membrane antibody; C507905:Jak1 protein, mouse; C507935:Jak3 protein, mouse; D053613:Janus Kinase 1; D053616:Janus Kinase 3; D000072377:Syk Kinase; C000606897:Syk protein, mouse
keywords: IL-15; IL-2Rβ; glomerulonephritis; lymphocyte; podocyte; γC chain