CD11c+ dendritic cells are required for IL-33-mediated expansion of ST2+Foxp3+ regulatory T cells in vivo (P1075)

Abstract

Abstract IL-33 is an IL-1 cytokine that signals via ST2, which is expressed on T cells and myeloid cells. Although IL-33 promotes Th2 responses, its administration potently expands CD4+Foxp3+ regulatory T cells (Treg). We examined if IL-33 expands murine Treg directly or indirectly through its impact on CD11c+ DC. The ability of IL-33 to facilitate CD3/CD28-stimulated proliferation of wild-type (WT) or ST2-/- Treg was compared to IL-2. The impact of IL-33 on the capacity of DC to expand Treg was defined in vitro on bone marrow (BM)-generated DC from WT or ST2-/- mice and in vivo using CD11c-DTR BM chimeras administered diphtheria toxin (DT) to deplete CD11c+ cells during IL-33 treatment. The capacity of IL-33-expanded Treg from Foxp3-RFP reporter mice to suppress effector T cells was assessed. We found that IL-33 directly expands Treg in vitro, including an ST2+ subset absent from IL-2-treated cultures. IL-33-exposed DC generate ST2+ Treg from naïve T cells, and is dependent on ST2 expressed by DC. IL-33 failed to expand Treg in vivo, especially ST2+ Treg, in the absence of CD11c+ cells. In conclusion, IL-33 promotes the expansion of suppressive Foxp3+ Treg, including an ST2+ subset in vitro and in vivo. This results from IL-33 activity directly on Treg, but more significantly, indirectly through its impact on CD11c+ cells. These findings have important implications for further characterization of ST2+ Treg and the development of novel therapeutics aimed at promoting immune tolerance.