IL-12hi rapamycin-conditioned dendritic cells mediate IFN-?-dependent apoptosis of alloreactive CD4+ T cells in vitro and reduce lethal graft-versus-host disease.

ABSTRACT: Rapamycin (RAPA) inhibits the mechanistic target of rapamycin (mTOR), a crucial immune system regulator. Dendritic cells (DC) generated in RAPA (RAPA-DC) enrich for CD4(+) forkhead box p3 (FoxP3(+)) regulatory T cells and induce T cell apoptosis by an unknown mechanism. RAPA-DC also promote experimental allograft survival, yet paradoxically secrete increased IL-12, crucial for the generation of IFN-?(+) CD4(+) T cells. However, IFN-? is pro-apoptotic and IL-12-driven IFN-? inhibits experimental graft-versus-host disease (GVHD). We hypothesized that IL-12(hi) RAPA-DC would facilitate IFN-?-mediated apoptosis of alloreactive T cells and, unlike control (CTR)-DC, would reduce lethal GVHD. Following LPS stimulation, RAPA-DC exhibited decreased MHCII and co-stimulatory molecules and contained a significant population of CD86(lo) IL-12(hi) cells. Consistent with our hypothesis, both unstimulated and LPS-stimulated RAPA-DC enhanced alloreactive CD4(+) T cell apoptosis in culture. Augmented T cell apoptosis was ablated by IFN-? neutralization or using T cells lacking the IFN-? receptor, and it was associated with increased expression of Fas and cleaved caspase 8. DC production or responses to IFN-? were not important to increased apoptotic functions of RAPA-DC. LPS-stimulated IL-12p40(-/-) RAPA-DC induced lower levels of T cell apoptosis in culture, which was further decreased with addition of anti-IFN-?. Finally, whereas CTR-DC accelerated mortality from GVHD, LPS-treated RAPA-DC significantly prolonged host survival. In conclusion, increased apoptosis of allogeneic CD4(+) T cells induced by LPS-stimulated IL-12(hi) RAPA-DC is mediated in vitro through IFN-? and in part by increased IL-12 expression. Enhanced production of IL-12, the predominant inducer of IFN-? by immune cells, is a probable mechanism underlying the capacity of LPS-treated RAPA-DC to reduce GVHD.

SUBMITTER: Stenger EO 

PROVIDER: S-EPMC3964782 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature