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.
To cite this abstract in AMA style:Matta B, Mathews L, Rosborough B, Turnquist H. IL-33 Expands ST2+ Regulatory T Cells Promoting Allograft Survival Directly and Indirectly through Actions on Myeloid Dendritic Cells [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/il-33-expands-st2-regulatory-t-cells-promoting-allograft-survival-directly-and-indirectly-through-actions-on-myeloid-dendritic-cells/. Accessed June 20, 2021.
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