Flexibility of mouse classical and plasmacytoid-derived dendritic cells in directing T helper type 1 and 2 cell development: dependency on antigen dose and differential toll-like receptor ligation.
Distinct dendritic cell (DC) subsets have been suggested to be preprogrammed to direct either T helper cell (Th) type 1 or Th2 development, although more recently different pathogen products or stimuli have been shown to render these DCs more flexible. It is still unclear how distinct mouse DC subsets cultured from bone marrow precursors, blood, or their lymphoid tissue counterparts direct Th differentiation. We show that mouse myeloid and plasmacytoid precursor DCs (pDCs) cultured from bone marrow precursors and ex vivo splenic DC subsets can induce the development of both Th1 and Th2 effector cells depending on the dose of antigen. In general, high antigen doses induced Th1 cell development whereas low antigen doses induced Th2 cell development. Both cultured and ex vivo splenic plasmacytoid-derived DCs enhanced CD4(+) T cell proliferation and induced strong Th1 cell development when activated with the Toll-like receptor (TLR)9 ligand CpG, and not with the TLR4 ligand lipopolysaccharide (LPS). The responsiveness of plasmacytoid pDCs to CpG correlated with high TLR9 expression similarly to human plasmacytoid pDCs. Conversely, myeloid DCs generated with granulocyte/macrophage colony-stimulating factor enhanced Th1 cell development when stimulated with LPS as a result of their high level of TLR4 expression. Polarized Th1 responses resulting from high antigen dose were not additionally enhanced by stimulation of DCs by TLR ligands. Thus, the net effect of antigen dose, the state of maturation of the DCs together with the stimulation of DCs by pathogen-derived products, will determine whether a Th1 or Th2 response develops.
Boonstra
André
A
Division of Immunoregulation, The National Institute for Medical Research (NIMR), NW7 1AA London, United Kingdom. andre.boonstra@nimr.mrc.ac.uk
Asselin-Paturel
Carine
C
Gilliet
Michel
M
Crain
Chad
C
Trinchieri
Giorgio
G
Liu
Yong-Jun
YJ
O'Garra
Anne
A
D000818:Animals; D000941:Antigens / Q000276:immunology*; D002454:Cell Differentiation; D002455:Cell Division; D018899:CpG Islands / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D004306:Dose-Response Relationship, Immunologic; D029721:Drosophila Proteins; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D008070:Lipopolysaccharides / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology; D010950:Plasma Cells / Q000166:cytology / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D000941:Antigens; D029721:Drosophila Proteins; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors