title: A role for CD40-CD40 ligand interactions in the generation of type 1 cytokine responses in human leprosy.
abstract: The interaction of CD40 ligand (CD40L) expressed by activated T cells with CD40 on macrophages has been shown to be a potent stimulus for the production of IL-12, an obligate signal for generation of Th1 cytokine responses. The expression and interaction of CD40 and CD40L were investigated in human infectious disease using leprosy as a model. CD40 and CD40L mRNA and surface protein expression were predominant in skin lesions of resistant tuberculoid patients compared with the highly susceptible lepromatous group. IL-12 release from PBMC of tuberculoid patients stimulated with Mycobacterium leprae was partially inhibited by mAbs to CD40 or CD40L, correlating with Ag-induced up-regulation of CD40L on T cells. Cognate recognition of M. leprae Ag by a T cell clone derived from a tuberculoid lesion in the context of monocyte APC resulted in CD40L-CD40-dependent production of IL-12. In contrast, M. leprae-induced IL-12 production by PBMC from lepromatous patients was not dependent on CD40L-CD40 ligation, nor was CD40L up-regulated by M. leprae. Furthermore, IL-10, a cytokine predominant in lepromatous lesions, blocked the IFN-gamma up-regulation of CD40 on monocytes. These data suggest that T cell activation in situ by M. leprae in tuberculoid leprosy leads to local up-regulation of CD40L, which stimulates CD40-dependent induction of IL-12 in monocytes. The CD40-CD40L interaction, which is not evident in lepromatous leprosy, probably participates in the cell-mediated immune response to microbial pathogens.
authors.affiliation: Department of Medicine, Division of Dermatology, University of California School of Medicine, Los Angeles, CA 90095, USA.
authors.forename: P S
authors.initials: PS
authors.lastname: Yamauchi
authors.forename: J R
authors.initials: JR
authors.lastname: Bleharski
authors.forename: K
authors.initials: K
authors.lastname: Uyemura
authors.forename: J
authors.initials: J
authors.lastname: Kim
authors.forename: P A
authors.initials: PA
authors.lastname: Sieling
authors.forename: A
authors.initials: A
authors.lastname: Miller
authors.forename: H
authors.initials: H
authors.lastname: Brightbill
authors.forename: K
authors.initials: K
authors.lastname: Schlienger
authors.forename: T H
authors.initials: TH
authors.lastname: Rea
authors.forename: R L
authors.initials: RL
authors.lastname: Modlin
mesh_terms: D019013:CD40 Antigens / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D023201:CD40 Ligand; D002462:Cell Membrane / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D006801:Humans; D007111:Immunity, Cellular; D018664:Interleukin-12 / Q000096:biosynthesis; D015440:Leprosy, Lepromatous / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015441:Leprosy, Tuberculoid / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008024:Ligands; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D009166:Mycobacterium leprae / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
chemical_list: D019013:CD40 Antigens; D016207:Cytokines; D008024:Ligands; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D023201:CD40 Ligand; D018664:Interleukin-12