Th61 - The Tolerogenic Effects of IL-2 on T Regulatory Cells (Tregs) are TGF-β Dependent

We and others have previously shown that IL-2 is essential for TGF-β to convert naïve CD4⁺CD25^- T cells into CD4⁺CD25⁺Foxp3⁺ Tregs.  Here we extend this finding by showing that the tolerogenic effects of IL-2 on Tregs are TGF-β dependent.  Using IL-2-loaded nanoparticles (NPs) coated with anti-CD2 antibody (Ab) to target both T cells and NK cells, we recently identified the critical importance of TGF-β-producing NK cells in the induction of CD4⁺ and CD8⁺ Foxp3⁺ Tregs which prevented murine lupus-like disease.  Here we used anti-CD2 Ab-coated NPs to inhibit a human anti-mouse graft versus host disease (GVHD) that develops after transfer of human PBMC into immunodeficient NOD/SCID mice.  We found that NPs containing only IL-2 protected mice from GVHD 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 mice.  Thus, 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 is relevant to ongoing clinical trials that employ low-dose IL-2 or IL-2 muteins in SLE and other autoimmune diseases to numerically expand functional Tregs. Because lymphocyte production of TGF-β is decreased in SLE, this study suggests the need to correct the deficits of both IL-2 and TGF-β for the optimal induction and expansion of functional Tregs in the immunotherapeutic management of SLE and other immune-mediated disorders.