IL-33 expands suppressive CD11b+ Gr-1int and regulatory T cells (Treg) including ST2L+ Foxp3+ cells and mediates Treg-dependent promotion of cardiac allograft survival

摘要

IL-33 administration is associated with facilitation of Th type-2 (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 (Treg) in mice. IL-33 expands functional myeloid-derived suppressor cells (MDSC), -CD11b⁺ cells that exhibit intermediate (int) levels of Gr-1 and potent T cell suppressive function. Furthermore, IL-33 administration causes a St2-dependent expansion of suppressive CD4⁺ Foxp3⁺ Treg, including a ST2L⁺ population. IL-33 monotherapy following 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 Treg. 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⁺ Treg that underlie IL-33-mediated cardiac allograft survival.