Background: IL-33 is an IL-1 cytokine that signals via ST2, which is expressed on both T cells and myeloid cells. IL-33 has been ascribed Th2 promoting capacities through its action on ST2⁺ myeloid dendritic cells (mDC), however, IL-33 administration potently increases the number of CD4⁺Foxp3⁺ regulatory T cells (Treg), which promote cardiac allograft survival. We examined if IL-33 expands Treg by targeting them directly or indirectly through its actions on mDC. Methods: The ability of IL-33 to facilitate anti-CD3/CD28-stimulated proliferation of BALB/c wild-type (WT) or ST2^-/- CD4⁺CD25⁺ T cells was directly compared to IL-2 by flow cytometric analysis. Conversely, the impact of IL-33 on the Treg-expanding capacity of mDC was defined in vitro on mDC generated from BALB/c WT or ST2^-/- bone marrow and in vivo using CD11c-DTR B6 bone marrow chimeras administered diphtheria toxin (DT) to selectively deplete CD11c⁺ cells during IL-33 treatment. The capacity of flow-sorted or ex vivo expanded Foxp3⁺ T cells from Foxp3-RFP reporter mice to suppress CD3/CD28-stimulated proliferation and polarization of syngeneic T cells was also assessed. Results: IL-33 drives the proliferation of CD4⁺CD25⁺ Treg during CD3/CD28-stimulation. Interestingly, it is a population of suppressive ST2⁺ Foxp3⁺ cells, absent from IL-2-treated cultures, that is expanded by IL-33. Yet, IL-33-exposed mDC also generate an ST2⁺ population of CD4⁺Foxp3⁺ cells in interacting naÏve T cell populations. Importantly, although IL-33 can directly augment Treg proliferation, addition of IL-33 to ST2^-/- mDC cultures revealed that the most significant contribution of IL-33 to ST2⁺ Treg expansion results from the impact of IL-33 on mDC. This was further supported by the failure of administered IL-33 to expand Treg, especially ST2⁺ Treg, in the absence of CD11c⁺ mDC in vivo. Conclusions: IL-33, in addition to supporting Th2 responses, promotes the expansion of functional Foxp3⁺ Treg, including an ST2⁺ subset in vitro and in vivo. This results from IL-33 activity directly on ST2⁺CD4⁺CD25⁺ Treg, but more importantly, indirectly through ST2⁺CD11c⁺ cells. These findings have significant implications for the development of novel therapeutics aimed at promoting tolerance and regulating alloimmunity in transplantation.

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