title: Rapamycin and omega-1: mTOR-dependent and -independent Th2 skewing by human dendritic cells.
abstract: Recent reports have attributed an immunoregulatory role to the mammalian target of rapamycin (mTOR), a key serine/threonine protein kinase integrating input from growth factors and nutrients to promote cell growth and differentiation. In the present study, we investigated the role of the mTOR pathway in Th2 induction by human monocyte-derived dendritic cells (moDCs). Using a co-culture system of human lipopolysaccharide (LPS)-matured moDCs and allogeneic naive CD4(+) T cells, we show that inhibition of mTOR by the immunosuppressive drug rapamycin reduced moDC maturation and promoted Th2 skewing. Next, we investigated whether antigens from helminth parasites, the strongest natural inducers of Th2 responses, modulate moDCs via the mTOR pathway. In contrast to rapamycin, neither Schistosoma mansoni-soluble egg antigens (SEA) nor its major immunomodulatory component omega-1 affected the phosphorylation of S6 kinase (S6K) and 4E-binding protein 1 (4E-BP1), downstream targets of mTORC1. Finally, we found that the effects of rapamycin and SEA/omega-1 on Th2 skewing were additive, suggesting two distinct underlying molecular mechanisms. We conclude that conditioning human moDCs to skew immune responses towards Th2 can be achieved via an mTOR-dependent and -independent pathway triggered by rapamycin and helminth antigens, respectively.
authors.affiliation: Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Leonie
authors.initials: L
authors.lastname: Hussaarts
authors.forename: Hermelijn H
authors.initials: HH
authors.lastname: Smits
authors.forename: Gabriele
authors.initials: G
authors.lastname: Schramm
authors.forename: Alwin J
authors.initials: AJ
authors.lastname: van der Ham
authors.forename: Gerard C
authors.initials: GC
authors.lastname: van der Zon
authors.forename: Helmut
authors.initials: H
authors.lastname: Haas
authors.forename: Bruno
authors.initials: B
authors.lastname: Guigas
authors.forename: Maria
authors.initials: M
authors.lastname: Yazdanbakhsh
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000947:Antigens, Helminth / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology*; D004527:Egg Proteins / Q000276:immunology; D015801:Helminth Proteins / Q000276:immunology; D006801:Humans; D007519:Isoantigens / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D010750:Phosphoproteins / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D012550:Schistosoma mansoni / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism*; D058408:Th1-Th2 Balance / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000947:Antigens, Helminth; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D004527:Egg Proteins; D015801:Helminth Proteins; D007519:Isoantigens; D008070:Lipopolysaccharides; D010750:Phosphoproteins; C079442:gp50 protein, Schistosoma; C587622:omega-1 antigen, Schistosoma mansoni; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus