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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