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Glomerular common gamma chain confers B- and T-cell–independent protection against glomerulonephritis

Abstract : Crescentic glomerulonephritis (GN) 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, a thymic/nude mice and rats still develop severe renal disease. Our aim was to explore further the contribution of intrinsic renal cells in the development of T cell-independent GN lesions. We induced anti-GBM-GN in 3 strains of immunodeficient mice (Rag2-/-, Rag2 -/-Il2rg -/-and Rag2-/-Il2r b -/-) which are devoid of either T/B cells or T/B/NK cells. Rag2 -/- Il2rg -/- or Rag2 -/- Il2rb -/- mice harbor an additional deletion of either the common gamma chain (gC) or the interleukin -2 receptor β subunit (IL-2R β) respectively, impairing IL -15 signaling in particular. As expected, all these strains developed severe anti-GBM-GN. In addition, bone marrow replenishment experiments allowed us to deduce a protective role for the glomerular-expressed gC 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 immunodeficient mice (Rag2 -/- Il2rg -/- and Rag2 -/- Il2r b -/- ) compared to controls. IL-15 induces downstream activation of JAK1/3 and spleen tyrosine kinase (SYK) in primary cultured podocytes. IL-15-dependent JAK/SYK induction was impaired in the absence of gC or IL-2R β. Given that we found gC largely induced on podocytes during human glomerulonephritis, we propose that renal lesions are indeed modulated by intrinsic glomerular cells through the γ C/IL - 2R β receptor response, to date classically described only in immune cells
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Yosu Luque, Dominique Cathelin, Sophie Vandermeersch, Xiaoli Xu, Julie Sohier, et al.. Glomerular common gamma chain confers B- and T-cell–independent protection against glomerulonephritis. Kidney International, Nature Publishing Group, 2017, 91 (5), pp.1146 - 1158. ⟨10.1016/j.kint.2016.10.037⟩. ⟨pasteur-01930924⟩

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