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

• Published in: Blood 2010-06, Vol.115 (23), p.4758-4769
• Main Authors: Turnquist, Hēth R., Cardinal, Jon, Macedo, Camila, Rosborough, Brian R., Sumpter, Tina L., Geller, David A., Metes, Diana, Thomson, Angus W.
• Format: Article
• Language: English
• Subjects: Animals; B7-2 Antigen - genetics; B7-2 Antigen - immunology; B7-2 Antigen - metabolism; Biological and medical sciences; Cell Differentiation - drug effects; Cell Differentiation - genetics; Cell Differentiation - immunology; Dendritic Cells - immunology; Dendritic Cells - metabolism; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - immunology; Forkhead Transcription Factors - metabolism; Glycogen Synthase Kinase 3 - genetics; Glycogen Synthase Kinase 3 - immunology; Glycogen Synthase Kinase 3 - metabolism; Hematologic and hematopoietic diseases; Humans; Immunobiology; Inflammation - genetics; Inflammation - immunology; Inflammation - metabolism; Interleukin-12 - genetics; Interleukin-12 - immunology; Interleukin-12 - metabolism; Interleukin-12 Subunit p40 - genetics; Interleukin-12 Subunit p40 - immunology; Interleukin-12 Subunit p40 - metabolism; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - immunology; Intracellular Signaling Peptides and Proteins - metabolism; Lipopolysaccharides - pharmacology; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Knockout; Myeloid Cells - immunology; Myeloid Cells - metabolism; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - immunology; Protein-Serine-Threonine Kinases - metabolism; Signal Transduction - drug effects; Signal Transduction - genetics; Signal Transduction - immunology; Th1 Cells - immunology; Th1 Cells - metabolism; Toll-Like Receptors - genetics; Toll-Like Receptors - immunology; Toll-Like Receptors - metabolism; TOR Serine-Threonine Kinases
• ISSN: 0006-4971; 1528-0020
• 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 CD86lo immature DCs. High IL-12p40/p70 production by CD86lo 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.