IL-33 Expands ST2+ Regulatory T Cells Promoting Allograft Survival Directly and Indirectly through Actions on Myeloid Dendritic Cells
Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA
Surgery, University of Pittsburgh, Pittsburgh, PA
Immunology, University of Pittsburgh, Pittsburgh, PA
Meeting: 2013 American Transplant Congress
Abstract number: 440
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 December 2, 2024.« Back to 2013 American Transplant Congress