ESAT-6 from <i>Mycobacterium tuberculosis</i> inhibits T cell IFN-γ production through p38 MAP kinase pathway (56.28)

Abstract We reported previously that ESAT-6 from Mycobacterium tuberculosis directly inhibits human T cell IFN-γ production and proliferation in response to stimulation with anti-CD3 plus anti-CD28. To determine the mechanism of this effect, we treated T-cells with kinase inhibitors before stimulation in the presence of ESAT-6. Only the p38 MAPK inhibitor, SB203580, abrogated ESAT-6-mediated inhibition of IFN-γ production in a dose-dependent manner. In contrast, 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, as an AKT inhibitor did not affect ESAT-6 inhibition of T cell IFN-γ production and proliferation, ruling out the possible off target effect of SB203580 through AKT. ESAT-6 did not expand FoxP3+ T regulatory cells, suggesting that Tregs do not play a role in ESAT-6 inhibition of T cell IFN-γ production. Incubation of T cells with ESAT-6 induced phosphorylation and increased functional p38 MAPK activity, but not activation of ERK or JNK. Silencing of p38α MAPK with siRNA rendered T-cells resistant to ESAT-6 inhibition of IFN-γ production. Taken together, our results demonstrated that ESAT-6 inhibits T cell IFN-γ production in a p38 MAPK-dependent manner.