title: Leishmania exosomes modulate innate and adaptive immune responses through effects on monocytes and dendritic cells.
abstract: We investigated the properties of leishmania exosomes with respect to influencing innate and adaptive immune responses. Exosomes from Leishmania donovani modulated human monocyte cytokine responses to IFN-γ in a bimodal fashion by promoting IL-10 production and inhibiting that of TNF-α. Moreover, these vesicles were inhibitory with respect to cytokine responses (IL-12p70, TNF-α, and IL-10) by human monocyte-derived dendritic cells. Exosomes from wild-type (WT) L. donovani failed to prime monocyte-derived dendritic cells to drive the differentiation of naive CD4 T cells into IFN-γ-producing Th1 cells. In contrast, vesicles from heat shock protein (HSP)100(-/-) L. donovani showed a gain-of-function and proinflammatory phenotype and promoted the differentiation of naive CD4 lymphocytes into Th1 cells. Proteomic analysis showed that exosomes from WT and HSP100(-/-) leishmania had distinct protein cargo, suggesting that packaging of proteins into exosomes is dependent in part on HSP100. Treatment of C57BL/6 mice with WT L. donovani exosomes prior to challenge with WT organisms exacerbated infection and promoted IL-10 production in the spleen. In contrast, HSP100(-/-) exosomes promoted spleen cell production of IFN-γ and did not adversely affect hepatic parasite burdens. Furthermore, the proparasitic properties of WT exosomes were not species specific because BALB/c mice exposed to Leishmania major exosomes showed increased Th2 polarization and exacerbation of disease in response to infection with L. major. These findings demonstrate that leishmania exosomes are predominantly immunosuppressive. Moreover, to our knowledge, this is the first evidence to suggest that changes in the protein cargo of exosomes may influence the impact of these vesicles on myeloid cell function.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Judith Maxwell
authors.initials: JM
authors.lastname: Silverman
authors.forename: Joachim
authors.initials: J
authors.lastname: Clos
authors.forename: Eva
authors.initials: E
authors.lastname: Horakova
authors.forename: Adele Y
authors.initials: AY
authors.lastname: Wang
authors.forename: Martina
authors.initials: M
authors.lastname: Wiesgigl
authors.forename: Isabelle
authors.initials: I
authors.lastname: Kelly
authors.forename: Miriam A
authors.initials: MA
authors.lastname: Lynn
authors.forename: W Robert
authors.initials: WR
authors.lastname: McMaster
authors.forename: Leonard J
authors.initials: LJ
authors.lastname: Foster
authors.forename: Megan K
authors.initials: MK
authors.lastname: Levings
authors.forename: Neil E
authors.initials: NE
authors.lastname: Reiner
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology*; D000818:Animals; D000953:Antigens, Protozoan / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002469:Cell Separation; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000382:microbiology*; D015180:Electrophoresis, Gel, Two-Dimensional; D049071:Endopeptidase Clp; D055354:Exosomes / Q000276:immunology*; D005434:Flow Cytometry; D006360:Heat-Shock Proteins / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D007893:Leishmania donovani / Q000276:immunology* / Q000378:metabolism; D007896:Leishmaniasis / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology / Q000382:microbiology*; D015800:Protozoan Proteins / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology
chemical_list: D000953:Antigens, Protozoan; D016207:Cytokines; D006360:Heat-Shock Proteins; D015800:Protozoan Proteins; D049071:Endopeptidase Clp; C095049:ClpB protein, Leishmania