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

• Published in: The Journal of immunology (1950) 2011-11, Vol.187 (9), p.4598-4610
• Main Authors: Turnquist, Heth R, Zhao, Zhenlin, Rosborough, Brian R, Liu, Quan, Castellaneta, Antonino, Isse, Kumiko, Wang, Zhiliang, Lang, Megan, Stolz, Donna Beer, Zheng, Xin Xiao, Demetris, A Jake, Liew, Foo Y, Wood, Kathryn J, Thomson, Angus W
• Format: Article
• Language: English
• Subjects: Animals; Atherosclerosis - immunology; Atherosclerosis - prevention & control; CD11b Antigen - biosynthesis; Cell Differentiation - immunology; Cells, Cultured; Down-Regulation - immunology; Forkhead Transcription Factors - biosynthesis; Graft Survival - immunology; Heart Transplantation - immunology; Heart Transplantation - pathology; Interleukin-33; Interleukins - physiology; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Transgenic; Myeloid Cells - cytology; Myeloid Cells - immunology; Myeloid Cells - metabolism; Receptors, Chemokine - biosynthesis; Receptors, Interleukin-1 - biosynthesis; T-Lymphocyte Subsets - cytology; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; T-Lymphocytes, Regulatory - cytology; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism
• ISSN: 1550-6606
• DOI: 10.4049/jimmunol.1100519

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.