title: Dendritic cell differentiation state and their interaction with NKT cells determine Th1/Th2 differentiation in the murine model of Leishmania major infection.
abstract: Recent reports demonstrated that dendritic cells (DC) sense inflammatory and microbial signals differently, redefining their classical subdivision into an immature endocytic and a mature Ag-presenting differentiation stage. Although both signals induce DC maturation by up-regulating MHC class II and costimulatory molecules, only TLR signals such as LPS are able to trigger proinflammatory cytokine secretion by DCs, including Th1-polarizing IL-12. Here, we explored the murine Leishmania major infection model to examine the CD4(+) T cell response induced by differentially matured DCs. When partially matured TNF-DCs were injected into BALB/c mice before infection, the mice failed to control L. major infection and developed a Th2 response which was dependent on IL-4Ralpha signaling. In contrast, injections of fully matured LPS+CD40-DCs induced a Th1 response controlling the infection. Pulsing DCs with a lysate of L. major did not affect DC maturation with TNF-alpha or LPS+anti-CD40. When the expression of different Notch ligands on DCs was analyzed, we found increased expression of Th2-promoting Jagged2 in TNF-DCs, whereas LPS+CD40-DCs up-regulated the Th1-inducing Delta4 and Jagged1 molecules. The Th2 polarization induced by TNF-DCs required interaction with CD1d-restricted NKT cells. However, NKT cell activation by L. major lysate-pulsed DCs was not affected by blockade of the endogenous glycolipid, suggesting exchange with exogenous parasite-derived CD1 glycolipid Ag. In sum, the differentiation stage of DCs as well as their interaction with NKT cells determines Th1/Th2 differentiation. These results have generic implications for the understanding of DC-driven Th cell responses and the development of improved DC vaccines against leishmaniasis.
authors: Department of Dermatology, University Hospital Erlangen, Erlangen, Germany. carsten.wiethe@derma.imed.uni-erlangen.de
authors: Carsten
authors: C
authors: Wiethe
authors: Andrea
authors: A
authors: Debus
authors: Markus
authors: M
authors: Mohrs
authors: Alexander
authors: A
authors: Steinkasserer
authors: Manfred
authors: M
authors: Lutz
authors: André
authors: A
authors: Gessner
mesh_terms: D000818:Animals; D018949:Antigens, CD1 / Q000378:metabolism; D055610:Antigens, CD1d; D002454:Cell Differentiation / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology*; D004195:Disease Models, Animal; D018320:Leishmania major / Q000276:immunology*; D007896:Leishmaniasis / Q000276:immunology / Q000469:parasitology; D008024:Ligands; D051379:Mice; D051880:Receptors, Notch / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
chemical_list: D018949:Antigens, CD1; D055610:Antigens, CD1d; D016207:Cytokines; D008024:Ligands; D051880:Receptors, Notch