IL-33 directly supports the proliferation of suppressive, naturally-occurring regulatory T cells expressing the IL-33 receptor, ST2 (161.1)

Abstract

Abstract Overview: Both IL-33 and its receptor, ST2, have been ascribed T helper type-2 (Th2) response promoting capacities. However, IL-33 increases splenic CD4+ forkhead box P3 (Foxp3)+ regulatory T cells (Treg) and post-transplant IL-33 monotherapy mediates a Treg-dependent prolongation of experimental cardiac allograft survival. As such, we addressed whether IL-33 directly targets Treg to support their expansion or suppressive function. Methods: The ability of recombinant IL-33 to facilitate anti-CD3/CD28-stimulated proliferation of BALB/c St2+/+ or St2-/- CD4+ CD25+ T cells was compared to IL-2. Following stimulation, Treg phenotype was defined by flow cytometry and their capacity to suppress naive T cell proliferation determined in bead-based suppression assays. Results: Following 3-4 days of culture, both cytokines promoted significant Treg proliferation vs. CD3/CD28 stimulation alone. However, IL-33 facilitated the expansion of a population ST2+ Foxp3+ cells that were absent from IL-2-treated cultures. Both IL-2 and IL-33-exposed Treg cultures exhibited suppressive activity. Conclusions: We identify the previously unreported capacity of IL-33 for direct expansion of Treg. Also, our data reveal that ST2, in addition to being expressed on Th2 cells, is found on an IL-33-expanded subset of suppressive Treg. These findings have significant implications for the therapeutic use of IL-33 to expand Treg, -cells critically important to tolerance and organ allograft survival.