Abstract
An acquired deficiency of interleukin-2 (IL-2) and related disturbances in regulatory T cell (Treg) homeostasis play an important role in the pathogenesis of systemic lupus erythematosus (SLE). Low-dose IL-2 therapy was shown to restore Treg homeostasis in patients with active SLE and its clinical efficacy is currently evaluated in clinical trials. Lupus nephritis (LN), a challenging organ manifestation in SLE, is characterized by the infiltration of pathogenic CD4+ T cells into the inflamed kidney. However, the role of the Treg-IL-2 axis in the pathogenesis of LN and the mode of action of IL-2 therapy in the inflamed kidneys are still poorly understood. Using the (NZB × NZW) F1 mouse model of SLE we studied whether intrarenal Treg are affected by a shortage of IL-2 in comparison with lymphatic organs and whether and how intrarenal T cells and renal inflammation can be influenced by IL-2 therapy. We found that intrarenal Treg show phenotypic signs that are reminiscent of IL-2 deprivation in parallel to a progressive hyperactivity of intrarenal conventional CD4+ T cells (Tcon). Short-term IL-2 treatment of mice with active LN induced an expansion the intrarenal Treg population whereas long-term IL-2 treatment reduced the activity and proliferation of intrarenal Tcon, which was accompanied by a clinical and histological amelioration of LN. The association of these immune pathologies with IL-2 deficiency and their reversibility by IL-2 therapy provides important rationales for an IL-2-based immunotherapy of LN.
Highlights
Systemic lupus erythematosus (SLE) is a severe systemic autoimmune disease characterized by the breach of self-tolerance to nuclear autoantigens leading to inflammation and tissue destruction in multiple organ systems [1]
In the (NZB × NZW) F1 mouse model of lupus and in human SLE patients we found that an acquired deficiency of IL-2 caused a homeostatic disbalance between proliferating Treg and conventional CD4+ T cells (Tcon), which was accompanied by the loss of CD25 expression on Treg and an accelerated Tcon hyperactivity in lymphatic organs and peripheral blood [14,15]
We correlated the quantities of intrarenal Treg and Tcon with the corresponding histomorphological activity index (AI) and with the proteinuria index (PUI) in (NZB × NZW)
Summary
Systemic lupus erythematosus (SLE) is a severe systemic autoimmune disease characterized by the breach of self-tolerance to nuclear autoantigens leading to inflammation and tissue destruction in multiple organ systems [1]. CD4+ T cells that belong to the Th1 lineage infiltrate the inflamed kidneys and are a predictor for the degree of renal inflammation in patients with LN [4,5,6,7]. Infiltrating CD4+ T cells play a crucial role for the initiation and perpetuation of inflammatory processes in LN. Studies that directly address the role of infiltrating immune cells in human organs are limited. The (NZB × NZW) F1 mouse model can be used as a suitable model to investigate the role of immune cells in the pathogenesis of LN [8]
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