title: Leishmania major phosphoglycans influence the host early immune response by modulating dendritic cell functions.
abstract: The precise role of Leishmania glycoconjugate molecules including phosphoglycans (PGs) and lipophosphoglycan (LPG) on host cellular responses is still poorly defined. Here, we investigated the interaction of Leishmania major LPG2 null mutant (lpg2(-)), which lacks both PGs and LPG, with dendritic cells (DCs) and the subsequent early immune response in infected mice. Surprisingly, the absence of phosphoglycans did not influence expression pattern of major histocompatibility complex class II (MHC II), CD40, CD80, and CD86 on DCs in vitro and in vivo. However, lpg2(-) L. major induced significantly higher production of interleukin-12p40 (IL-12p40) by infected bone marrow-derived DCs (BMDCs) than wild-type (WT) parasites in vitro. Furthermore, the production of IL-12p40 by draining lymph node cells from lpg2(-) mutant-infected mice was higher than those from WT L. major-infected mice. In model antigen presentation experiments, DCs from lpg2(-) mutant-infected mice induced more gamma interferon (IFN-gamma) and IL-2 production by Leishmania-specific T cells than those from WT-infected mice. Lymphocytes isolated from mice infected for 3 days with lpg2(-) parasites produce similar levels of IFN-gamma, but significantly less IL-4 and IL-10 than WT controls. Decreased IL-4 production was also seen in another general PG-deficient mutant lacking the Golgi UDP-galactose transporters (lpg5A(-) lpg5B(-)), but not with the lpg1(-) mutant lacking only LPG, thereby implicating PGs generally in the reduction of IL-4 production. Thus, Leishmania PGs influence host early immune response by modulating DC functions in a way that inhibits antigen presentation and promotes early IL-4 response, and their absence may impact the balance between Th1 and Th2 responses.
authors.affiliation: Department of Immunology, University of Manitoba, Winnipeg, Canada.
authors.forename: Dong
authors.initials: D
authors.lastname: Liu
authors.forename: Chahnaz
authors.initials: C
authors.lastname: Kebaier
authors.forename: Nazzy
authors.initials: N
authors.lastname: Pakpour
authors.forename: Althea A
authors.initials: AA
authors.lastname: Capul
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Beverley
authors.forename: Phillip
authors.initials: P
authors.lastname: Scott
authors.forename: Jude E
authors.initials: JE
authors.lastname: Uzonna
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D015703:Antigens, CD / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000469:parasitology*; D005260:Female; D006028:Glycosphingolipids / Q000172:deficiency; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D007155:Immunologic Factors / Q000276:immunology / Q000494:pharmacology*; D053762:Interleukin-12 Subunit p40 / Q000378:metabolism; D018320:Leishmania major / Q000737:chemistry* / Q000276:immunology*; D008565:Membrane Proteins / Q000172:deficiency; D051379:Mice; D008807:Mice, Inbred BALB C; D011134:Polysaccharides / Q000276:immunology / Q000494:pharmacology*; D015800:Protozoan Proteins; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D015703:Antigens, CD; D016207:Cytokines; D006028:Glycosphingolipids; D000949:Histocompatibility Antigens Class II; D007155:Immunologic Factors; D053762:Interleukin-12 Subunit p40; C095909:LPG2 protein, Leishmania; D008565:Membrane Proteins; D011134:Polysaccharides; D015800:Protozoan Proteins