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

Immune control of Mycobacterium tuberculosis depends on interferon gamma (IFN-gamma)-producing CD4(+) lymphocytes. Previous studies have shown that T cells from patients with tuberculosis produce less IFN-gamma, compared with healthy donors, in response to mycobacterial antigens, although IFN-gamma responses to mitogens are preserved. In this work, we found that M. tuberculosis-induced IFN-gamma 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-gamma-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-gamma 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-gamma production in response to M. tuberculosis, a pathway that is defective in patients with tuberculosis.