Phosphorylation of Mitogen-Activated Protein Kinases Contributes to Interferon γ Production in Response to Mycobacterium tuberculosis

PASQUINELLI VIRGINIA; ANA I. ROVETTA; IVANA B. ÁLVAREZ; JAVIER JURADO; ROSA M MUSELLA; DOMINGO PALMERO; ALEJANDRO MALBRAN; BUKA SAMTEN; PETER BARNES; VERONICA E GARCIA

JOURNAL OF INFECTIOUS DISEASES

UNIV CHICAGO PRESS

Lugar: Chicago; Año: 2012

0022-1899

Immunity to M. tuberculosis is critically dependent on CD4+T cells, particularly IFN--producing lymphocytes, and reduced IFN- production is a marker of severe disease. Thus, elucidation of the mechanisms for reduced IFN- secretion in tuberculosis patients is crucial to gain insight into the immune response against this intracellular pathogen. To this end, we investigated the role of mitogen-activated protein kinases (MAPK) in T-cell IFN- production in active tuberculosis. We demonstrated that both extracellular signal-regulated kinase (ERK) and p38 MAPKs mediate T-cell IFN- production against M. tuberculosis, and that their phosphorylation correlated with M. tuberculosis-induced IFN- production. Tuberculosis patients with low T-cell IFN- levels had delayed activation of ERK and p38, and patients with the poorest IFN- responses (low responders) had greater defects in MAPK activation than responsive tuberculosis patients (high responders). Moreover, most IFN-+T-cells expressed phosphorylated cAMP response element binding protein (CREB) and SLAM, and SLAM activation further increased ERK phosphorylation and IFN- secretion. However, SLAM activation failed to phosphorylate ERK in unresponsive tuberculosis patients, suggesting that they have defective signaling through SLAM, coupled with dysfunctional activation of ERK and p38 MAPKs. Thus, we identified a novel MAPK activation pathway in T cells that produce IFN- in response to M. tuberculosis.