title: Impaired dendritic cell differentiation of CD16-positive monocytes in tuberculosis: role of p38 MAPK.
abstract: Tuberculosis (TB) is one of the world's most pernicious diseases mainly due to immune evasion strategies displayed by its causative agent Mycobacterium tuberculosis (Mtb). Blood monocytes (Mos) represent an important source of DCs during chronic infections; consequently, the alteration of their differentiation constitutes an escape mechanism leading to mycobacterial persistence. We evaluated whether the CD16(+)/CD16(-) Mo ratio could be associated with the impaired Mo differentiation into DCs found in TB patients. The phenotype and ability to stimulate Mtb-specific memory clones DCs from isolated Mo subsets were assessed. We found that CD16(-) Mos differentiated into CD1a(+) DC-SIGN(high) cells achieving an efficient recall response, while CD16(+) Mos differentiated into a CD1a(-) DC-SIGN(low) population characterized by a poor mycobacterial Ag-presenting capacity. The high and sustained phosphorylated p38 expression observed in CD16(+) Mos was involved in the altered DC profile given that its blockage restored DC phenotype and its activation impaired CD16(-) Mo differentiation. Furthermore, depletion of CD16(+) Mos indeed improved the differentiation of Mos from TB patients toward CD1a(+) DC-SIGN(high) DCs. Therefore, Mos from TB patients are less prone to differentiate into DCs due to their increased proportion of CD16(+) Mos, suggesting that during Mtb infection Mo subsets may have different fates after entering the lungs.
authors.affiliation: IMEX-CONICET, Academia Nacional de Medicina, Buenos Aires, Argentina. luciana_balboa@hotmail.com
authors.forename: Luciana
authors.initials: L
authors.lastname: Balboa
authors.forename: María M
authors.initials: MM
authors.lastname: Romero
authors.forename: Evangelina
authors.initials: E
authors.lastname: Laborde
authors.forename: Carmen A
authors.initials: CA
authors.lastname: Sabio Y García
authors.forename: Juan I
authors.initials: JI
authors.lastname: Basile
authors.forename: Pablo
authors.initials: P
authors.lastname: Schierloh
authors.forename: Noemí
authors.initials: N
authors.lastname: Yokobori
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Musella
authors.forename: Jorge
authors.initials: J
authors.lastname: Castagnino
authors.forename: Silvia
authors.initials: S
authors.lastname: de la Barrera
authors.forename: María C
authors.initials: MC
authors.lastname: Sasiain
authors.forename: Mercedes
authors.initials: M
authors.lastname: Alemán
mesh_terms: D000328:Adult; D018949:Antigens, CD1 / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D005260:Female; D058851:GPI-Linked Proteins / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D009169:Mycobacterium tuberculosis / Q000276:immunology; D017452:Receptors, IgG / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology / Q000502:physiology; D014376:Tuberculosis / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D055815:Young Adult; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism*
chemical_list: D018949:Antigens, CD1; C419393:CD1a antigen; C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; D017452:Receptors, IgG; D048051:p38 Mitogen-Activated Protein Kinases