Phosphorylation of mitogen-activated protein kinases contributes to IFN-g production in response to Mycobacterium tuberculosis

PASQUINELLI V; ROVETTA AI; ALVAREZ IB; JURADO JO; ROSA M. MUSELLA; PALMERO D; MALBRÁN A; SAMTEN B; BARNES PF; GARCÍA VE

JOURNAL OF INFECTIOUS DISEASES

UNIV CHICAGO PRESS

Lugar: Chicago; Año: 2013 vol. 207 p. 340 - 350

0022-1899

Immune control of M. tuberculosis depends on IFN-g-producing CD4+ lymphocytes, and previous studies have shown that T-cells from tuberculosis patients produce less IFN-g in response to mycobacterial antigens than healthy donors, although IFN-g responses to mitogens are preserved. In this work, we found that M. tuberculosis-induced IFN-g 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-g+ T-cells expressed signaling lymphocyte activation molecule (SLAM), and SLAM activation further increased ERK phosphorylation. Interestingly, tuberculosis patients had delayed activation of ERK and p38, and this was most marked in patients with the poorest IFN-g responses (low responders). Besides, SLAM signaling failed to phosphorylate ERK in low responder patients. Our findings suggest that activation of p38 and ERK, in part through SLAM, mediates T-cell IFN-g production in response to M. tuberculosis, a pathway that is defective in tuberculosis patients.