title: Phosphorylation of mitogen-activated protein kinases contributes to interferon γ production in response to Mycobacterium tuberculosis.
abstract: Immune control of Mycobacterium tuberculosis depends on interferon γ (IFN-γ)-producing CD4(+) lymphocytes. Previous studies have shown that T cells from patients with tuberculosis produce less IFN-γ, compared with healthy donors, in response to mycobacterial antigens, although IFN-γ responses to mitogens are preserved. In this work, we found that M. tuberculosis-induced IFN-γ production by human T cells correlated with phosphorylation of the mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK), and p38. Moreover, the majority of IFN-γ-producing T cells expressed signaling lymphocyte activation molecule (SLAM), and SLAM activation further increased ERK phosphorylation. Interestingly, patients with tuberculosis had delayed activation of ERK and p38, and this was most marked in patients with the poorest IFN-γ responses (ie, low responders). Besides, SLAM signaling failed to phosphorylate ERK in low responders. Our findings suggest that activation of p38 and ERK, in part through SLAM, mediates T-cell IFN-γ production in response to M. tuberculosis, a pathway that is defective in patients with tuberculosis.
authors.affiliation: Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Instituto de Química Biológica, Ciencias Exactas y Naturales, Consejo Nacional de Investigaciones Científicas y Tecnológicas, Buenos Aires, Argentina.
authors.forename: Virginia
authors.initials: V
authors.lastname: Pasquinelli
authors.forename: Ana I
authors.initials: AI
authors.lastname: Rovetta
authors.forename: Ivana B
authors.initials: IB
authors.lastname: Alvarez
authors.forename: Javier O
authors.initials: JO
authors.lastname: Jurado
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Musella
authors.forename: Domingo J
authors.initials: DJ
authors.lastname: Palmero
authors.forename: Alejandro
authors.initials: A
authors.lastname: Malbrán
authors.forename: Buka
authors.initials: B
authors.lastname: Samten
authors.forename: Peter F
authors.initials: PF
authors.lastname: Barnes
authors.forename: Verónica E
authors.initials: VE
authors.lastname: García
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis*; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D010766:Phosphorylation; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D013601:T-Lymphocytes / Q000276:immunology*; D014397:Tuberculosis, Pulmonary / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D011956:Receptors, Cell Surface; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D007371:Interferon-gamma; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases