title: IL-33 expands suppressive CD11b+ Gr-1(int) and regulatory T cells, including ST2L+ Foxp3+ cells, and mediates regulatory T cell-dependent promotion of cardiac allograft survival.
abstract: IL-33 administration is associated with facilitation of Th2 responses and cardioprotective properties in rodent models. However, in heart transplantation, the mechanism by which IL-33, signaling through ST2L (the membrane-bound form of ST2), promotes transplant survival is unclear. We report that IL-33 administration, while facilitating Th2 responses, also increases immunoregulatory myeloid cells and CD4(+) Foxp3(+) regulatory T cells (Tregs) in mice. IL-33 expands functional myeloid-derived suppressor cells, CD11b(+) cells that exhibit intermediate (int) levels of Gr-1 and potent T cell suppressive function. Furthermore, IL-33 administration causes an St2-dependent expansion of suppressive CD4(+) Foxp3(+) Tregs, including an ST2L(+) population. IL-33 monotherapy after fully allogeneic mouse heart transplantation resulted in significant graft prolongation associated with increased Th2-type responses and decreased systemic CD8(+) IFN-γ(+) cells. Also, despite reducing overall CD3(+) cell infiltration of the graft, IL-33 administration markedly increased intragraft Foxp3(+) cells. Whereas control graft recipients displayed increases in systemic CD11b(+) Gr-1(hi) cells, IL-33-treated recipients exhibited increased CD11b(+) Gr-1(int) cells. Enhanced ST2 expression was observed in the myocardium and endothelium of rejecting allografts, however the therapeutic effect of IL-33 required recipient St2 expression and was dependent on Tregs. These findings reveal a new immunoregulatory property of IL-33. Specifically, in addition to supporting Th2 responses, IL-33 facilitates regulatory cells, particularly functional CD4(+) Foxp3(+) Tregs that underlie IL-33-mediated cardiac allograft survival.
authors.affiliation: Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Heth R
authors.initials: HR
authors.lastname: Turnquist
authors.forename: Zhenlin
authors.initials: Z
authors.lastname: Zhao
authors.forename: Brian R
authors.initials: BR
authors.lastname: Rosborough
authors.forename: Quan
authors.initials: Q
authors.lastname: Liu
authors.forename: Antonino
authors.initials: A
authors.lastname: Castellaneta
authors.forename: Kumiko
authors.initials: K
authors.lastname: Isse
authors.forename: Zhiliang
authors.initials: Z
authors.lastname: Wang
authors.forename: Megan
authors.initials: M
authors.lastname: Lang
authors.forename: Donna Beer
authors.initials: DB
authors.lastname: Stolz
authors.forename: Xin Xiao
authors.initials: XX
authors.lastname: Zheng
authors.forename: A Jake
authors.initials: AJ
authors.lastname: Demetris
authors.forename: Foo Y
authors.initials: FY
authors.lastname: Liew
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Wood
authors.forename: Angus W
authors.initials: AW
authors.lastname: Thomson
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000276:immunology / Q000517:prevention & control; D039481:CD11b Antigen / Q000096:biosynthesis*; D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000096:biosynthesis*; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D000067596:Interleukin-33; D007378:Interleukins / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D019707:Receptors, Chemokine / Q000096:biosynthesis; D017472:Receptors, Interleukin-1 / Q000096:biosynthesis; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
chemical_list: D039481:CD11b Antigen; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C503133:Gr-1 protein, mouse; C506535:Il33 protein, mouse; D000067596:Interleukin-33; D007378:Interleukins; D019707:Receptors, Chemokine; D017472:Receptors, Interleukin-1; C530318:ST2L protein, mouse