title: Mycobacteria exploit p38 signaling to affect CD1 expression and lipid antigen presentation by human dendritic cells.
abstract: Group I CD1 proteins are specialized antigen-presenting molecules that present both microbial and self lipid antigens to CD1-restricted alpha/beta T lymphocytes. The production of high levels of gamma interferon and lysis of infected macrophages by lipid-specific T lymphocytes are believed to play pivotal roles mainly in the defense against mycobacterial infections. We previously demonstrated that Mycobacterium tuberculosis and bacillus Calmette-Guérin (Mycobacterium bovis BCG) induce human monocytes to differentiate into CD1- dendritic cells (DC), which cannot present lipid antigens to specific T cells. Here, we show that in human monocytes mycobacteria trigger phosphorylation of p38 mitogen-activated protein kinase to inhibit CD1 expression in DC derived from infected monocytes. Pretreatment with a specific p38 inhibitor renders monocytes insensitive to mycobacterial subversion and allows them to differentiate into CD1+ DC, which are fully capable of presenting lipid antigens to specific T cells. We also report that one of the pathogen recognition receptors triggered by BCG to activate p38 is complement receptor 3 (CR3), as shown by reduced p38 phosphorylation and partial reestablishment of CD1 membrane expression obtained by CR3 blockade before infection. In conclusion, we propose that p38 signaling is a novel pathway exploited by mycobacteria to affect the expression of CD1 antigen-presenting cells and avoid immune recognition.
authors.affiliation: Dipartimento di Malattie Infettive, Parassitarie e Immunomediate, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Roma, Italy.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Gagliardi
authors.forename: Raffaela
authors.initials: R
authors.lastname: Teloni
authors.forename: Federico
authors.initials: F
authors.lastname: Giannoni
authors.forename: Sabrina
authors.initials: S
authors.lastname: Mariotti
authors.forename: Maria Elena
authors.initials: ME
authors.lastname: Remoli
authors.forename: Valeria
authors.initials: V
authors.lastname: Sargentini
authors.forename: Melissa
authors.initials: M
authors.lastname: Videtta
authors.forename: Manuela
authors.initials: M
authors.lastname: Pardini
authors.forename: Gennaro
authors.initials: G
authors.lastname: De Libero
authors.forename: Eliana Marina
authors.initials: EM
authors.lastname: Coccia
authors.forename: Roberto
authors.initials: R
authors.lastname: Nisini
mesh_terms: D051698:Activating Transcription Factor 2 / Q000378:metabolism; D017951:Antigen Presentation / Q000276:immunology*; D018949:Antigens, CD1 / Q000096:biosynthesis*; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008055:Lipids / Q000276:immunology; D016177:Macrophage-1 Antigen / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000382:microbiology*; D009161:Mycobacterium / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D018949:Antigens, CD1; D004791:Enzyme Inhibitors; D008055:Lipids; D016177:Macrophage-1 Antigen; D012333:RNA, Messenger; D048051:p38 Mitogen-Activated Protein Kinases