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1901 The Tolerogenic Effects of IL-2 on T Regulatory Cells (Tregs) are TGF-β Dependent
  1. Antonio La Cava1 and
  2. David A Horwitz2,3
  1. 1Department of Medicine, University of California Los Angeles, Los Angeles, CA
  2. 2General Nanotherapeutics, Santa Monica, CA
  3. 3Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA


Background We and others have previously shown that IL-2 is essential for TGF-β to allow conversion of naïve CD4+CD25- T cells into CD4+CD25+Foxp3+ Tregs. To further those studies, we recently used IL-2- loaded nanoparticles (NPs) coated with anti-CD2 antibody (Ab) to target both T cells and NK cells in lupus mice, identifying a key role of a population of TGF-β-producing NK cells in the induction of the CD4+ and CD8+ Foxp3+ Tregs that prevented disease.

Methods Anti-CD2 Ab-coated NPs made of polylactic-co-glycolic acid (PLGA) and encapsulating IL-2 or IL-2/TGF-β were used to inhibit a lupus-like disease characterized by a human anti-mouse graft versus host disease (GVHD) that develops after transfer of human PBMCs into immunodeficient NOD SCID mice.

Research NPs containing only IL-2 protected mice from autoimmune disease similarly to NPs containing both IL-2 and TGF-β. Remarkably, the blockade of TGF-β signaling with an ALK-V inhibitor not only abolished the protective effects of the NPs but also reduced the survival of the diseased mice.

Conclusions In the absence of TGF-β, IL-2 induces pathogenic T effector cells instead of promoting the induction of protective Tregs. This key role of TGF-β in the induction of Tregs has relevance for the ongoing clinical trials that employ low-dose IL-2 or IL-2 muteins in SLE and other autoimmune diseases to expand functional Tregs. Since lymphocyte production of TGF-β is decreased in SLE, our study suggests that in the immunotherapeutic management of SLE, one needs to correct the deficits of both IL-2 and TGF-β to optimally induce and expand functional Tregs.

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