Abstract Early secreted antigenic target of 6 kD (ESAT-6) is a M. tuberculosis protein that induces protective immunity against tuberculosis in animal models and is a putative vaccine candidate. However, this protein also contributes to virulence and inhibits immune cells activation. In this study, we evaluated the effects of ESAT-6 on the function of human dendritic cells. Immature dendritic cells (DC) were induced from monocytes cultured with GM-CSF plus IL-4. ESAT-6 inhibited IL-12, but promotes IL-23 production of DC during maturation stimulated by LPS plus CD40L. This is correlated with downregulated IL-12p35 and upregulated IL-23p19 transcripts, respectively. ESAT-6 did not affect the induction of TNF-α, IL-6 and IL-8 from DC during maturation. ESAT-6 also inhibited upregulation of co-stimulatory molecules, CD80, CD86, HLA-DR, in both monocyte derived DC and myeloid DC freshly purified from human blood, in response to stimulation of LPS plus CD40L. DC pretreated with ESAT-6 induced less IL-2 and IFN-γ production in mixed lymphocyte reactions, and stimulated less IFN-γ, but more IL-17 production from M.tuberculosis responsive T cells compared to nontreated DC. Blocking TLR1/2 on DC or removing 20 amino acids in C-terminus did not ablate the inhibition of ESAT-6 on IL-12 production. We conclude that ESAT-6 enhances IL-23 production at the expense of IL-12 in a TLR2 independent mechanism, which favors Th17 over Th1 activation. (Supported by the NIH grants AI082335 and AI063514)
Discussion(0)
No comments yet. Be the first to comment.