The Mycobacterium tuberculosis Early Secreted Antigenic Target of 6 kDa Inhibits T Cell Interferon-γ Production through the p38 Mitogen-activated Protein Kinase Pathway

• DOI: 10.1074/jbc.m111.234062
• Publication Date: 2011-05-18T02:06:06Z
• Authors: Hui Peng; Xisheng Wang; Peter F. Barnes; Hua Tang; James C. Townsend; Buka Samten
• Keywords: 0301 basic medicine; Antigens, Bacterial; 0303 health sciences; MAP Kinase Kinase 4; Pyridines; T-Lymphocytes; Interleukin-17; Imidazoles; Mycobacterium tuberculosis; p38 Mitogen-Activated Protein Kinases; Interleukin-10; 3. Good health; Interferon-gamma; 03 medical and health sciences; Bacterial Proteins; Latent Tuberculosis; Humans; Gene Silencing; Enzyme Inhibitors; Proto-Oncogene Proteins c-akt; Cells, Cultured; Cell Proliferation

We reported previously that the early secreted antigenic target of 6 kDa (ESAT-6) from Mycobacterium tuberculosis directly inhibits human T cell IFN-γ production and proliferation in response to stimulation with anti-CD3 and anti-CD28. To determine the mechanism of this effect, we treated T cells with kinase inhibitors before stimulation with ESAT-6. Only the p38 MAPK inhibitor, SB203580, abrogated ESAT-6-mediated inhibition of IFN-γ production in a dose-dependent manner. SB203580 did not reverse ESAT-6-mediated inhibition of IL-17 and IL-10 production, suggesting a specific effect of SB203580 on IFN-γ production. SB203580 did not act through inhibition of AKT (PKB) as an AKT inhibitor did not affect ESAT-6 inhibition of T cell IFN-γ production and proliferation. ESAT-6 did not reduce IFN-γ production by expanding FoxP3(+) T regulatory cells. Incubation of T cells with ESAT-6 induced phosphorylation and increased functional p38 MAPK activity, but not activation of ERK or JNK. Incubation of peripheral blood mononuclear cells with ESAT-6 induced activation of p38 MAPK, and inhibition of p38 MAPK with SB203580 reversed ESAT-6 inhibition of M. tuberculosis-stimulated IFN-γ production by peripheral blood mononuclear cells from subjects with latent tuberculosis infection. Silencing of p38α MAPK with siRNA rendered T cells resistant to ESAT-6 inhibition of IFN-γ production. Taken together, our results demonstrate that ESAT-6 inhibits T cell IFN-γ production in a p38 MAPK-dependent manner.