mTOR and GSK-3 shape the CD4(+) T-cell stimulatory and differentiation capacity of myeloid DCs after exposure to LPS

作者：Turnquist Heth R; Cardinal Jon; Macedo Camila; Ro**orough Brian R; Sumpter Tina L; Geller David A; Metes Diana; Thomson Angus W^*

来源：Blood, 2010, 115(23): 4758-4769.

DOI：10.1182/blood-2009-10-251488

Prolonged inhibition of the kinase, mammalian target of rapamycin (mTOR), during myeloid dendritic cell (DC) generation confers resistance to maturation. Recently, however, mTOR inhibition immediately before Toll-like receptor ligation has been found to exert proinflammatory effects on myeloid cells, notably enhanced IL-12p40/p70 production. We show, for the first time, that mouse or human DCs generated under mTOR inhibition exhibit markedly enhanced IL-12p70 production after lipopolysaccharide (LPS) stimulation, despite impaired costimulatory molecule expression and poor T-cell stimulatory ability. Consistent with this finding, we reveal that increased IL-12p40 production occurs predominantly in CD86(lo) immature DCs. High IL-12p40/p70 production by CD86(lo) DC resulted from failed down-regulation of glycogen synthase kinase-3 (GSK-3) activity and could not be ascribed to enhanced Akt function. Despite high IL-12p70 secretion, rapamycin-conditioned, LPS-stimulated DCs remained poor T-cell stimulators, failing to enhance allogeneic Th1 cell responses. We also report that inhibition of GSK-3 impedes the ability of LPS-stimulated DCs to induce forkhead box p3 in CD4(+)CD25(-) T cells, as does the absence of IL-12p40/p70. Thus, GSK-3 activity in DC is regulated via signaling linked to mTOR and modulates their capacity both to produce IL-12p40/p70 and induce forkhead box p3 in CD4(+) T cells under inflammatory conditions. (Blood. 2010;115(23):4758-4769)

• 出版日期2010-6-10