title: IL-33 is an unconventional Alarmin that stimulates IL-2 secretion by dendritic cells to selectively expand IL-33R/ST2+ regulatory T cells.
abstract: IL-33 is a recently characterized IL-1 family member that is proposed to function as an alarmin, or endogenous signal of cellular damage, as well as act as a pleiotropic cytokine. The ability of IL-33 to potentiate both Th1 and Th2 immunity supports its role in pathogen clearance and disease immunopathology. Yet, IL-33 restrains experimental colitis and transplant rejection by expanding regulatory T cells (Treg) via an undefined mechanism. We sought to determine the influence of IL-33 on hematopoietic cells that drives Treg expansion and underlies the therapeutic benefit of IL-33 administration. In this study, we identify a feedback loop in which conventional mouse CD11c(+) dendritic cells (DC) stimulated by IL-33 secrete IL-2 to selectively expand IL-33R(ST2(+))- suppressive CD4(+)Foxp3(+) Treg. Interestingly, this occurs in the absence of classical DC maturation, and DC-derived (innate) IL-2 increases ST2 expression on both DC and interacting Treg. ST2(+) Treg represent an activated subset of Foxp3(+) cells, demonstrated to be ICOS(high)CD44(high) compared with their ST2(-) counterparts. Furthermore, although studies have shown that IL-33-exposed DC promote Th2 responses, we reveal that ST2(+) DC are required for IL-33-mediated in vitro and in vivo Treg expansion. Thus, we have uncovered a relationship between IL-33 and innate IL-2 that promotes the selective expansion of ST2(+) Treg over non-Treg. These findings identify a novel regulatory pathway driven by IL-33 in immune cells that may be harnessed for therapeutic benefit or for robust expansion of Treg in vitro and in vivo.
authors.affiliation: Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261;
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Matta
authors.affiliation: Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261;
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Lott
authors.affiliation: Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; Department of Infectious Diseases and Microbiology, University of Pittsburgh School of Public Health, Pittsburgh, PA 15261;
authors.forename: Lisa R
authors.initials: LR
authors.lastname: Mathews
authors.affiliation: Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; Department of Cardiovascular Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China;
authors.forename: Quan
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; Medical Scientist Training Program, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; Graduate Training Program in Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261;
authors.forename: Brian R
authors.initials: BR
authors.lastname: Rosborough
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455; and.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.affiliation: Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261 het5@pitt.edu.
authors.forename: Hēth R
authors.initials: HR
authors.lastname: Turnquist
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D060889:Inducible T-Cell Co-Stimulator Protein / Q000096:biosynthesis; D000072179:Interleukin-1 Receptor-Like 1 Protein; D007376:Interleukin-2 / Q000378:metabolism*; D000067596:Interleukin-33; D007378:Interleukins / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018123:Receptors, Interleukin / Q000096:biosynthesis; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
chemical_list: C476399:Cd44 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018960:Hyaluronan Receptors; C556694:Icos protein, mouse; C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D000072179:Interleukin-1 Receptor-Like 1 Protein; D007376:Interleukin-2; D000067596:Interleukin-33; D007378:Interleukins; D018123:Receptors, Interleukin