Early secreted antigen ESAT-6 of mycobacterium tuberculosis promotes protective T helper 17 cell responses in a toll-like receptor-2-dependent manner

Despite its relatively poor efficacy,bacillus calmette-guérin (bcg) has been used as a tuberculosis (tb) vaccine since its development in 1921. bcg induces robust t helper 1 (th1) immune responses but,for many individuals,this is not sufficient for host resistance against mycobacterium tuberculosis (m. tb) infection. here we provide evidence that early secreted antigenic target protein 6 (esat-6),expressed by the virulent m. tb strain h37rv but not by bcg,promotes vaccine-enhancing th17 cell responses. these activities of esat-6 were dependent on tlr-2/myd88 signalling and involved il-6 and tgf-β production by dendritic cells. thus,animals that were previously infected with h37rv or recombinant bcg containing the rd1 region (bcg::rd1) exhibited improved protection upon re-challenge with virulent h37rv compared with mice previously infected with bcg or rd1-deficient h37rv (h37rvδrd1). however,tlr-2 knockout (tlr-2-/-) animals neither showed th17 responses nor exhibited improved protection in response to immunization with h37rv. furthermore,h37rv and bcg::rd1 infection had little effect on the expression of the anti-inflammatory microrna-146a (mir146a) in dendritic cells (dcs),whereas bcg and h37rvδrd1 profoundly induced its expression in dcs. consistent with these findings,esat-6 had no effect on mir146a expression in uninfected dcs,but dramatically inhibited its upregulation in bcg-infected or lps-treated dcs. collectively,our findings indicate that,in addition to th1 immunity induced by bcg,rd1/esat-6-induced th17 immune responses are essential for optimal vaccine efficacy. © 2011 chatterjee et al.