Journal
JOURNAL OF INFECTIOUS DISEASES
Volume 207, Issue 2, Pages 340-350Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/infdis/jis672
Keywords
Tuberculosis; signaling; CREB; MAPK; IFN-gamma
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Funding
- Agencia Nacional de Promocion Cientifica y Tecnologica [PAE-PID-2007-00127, PICT 01384, PICT 01769]
- University of Buenos Aires [UBACYT X087, UBACYT 20020100100221]
- National Institutes of Health, National Institutes of Allergy and Infectious Diseases [R01 AI079007]
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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.
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