415057.fig.001
Figure 1: Stimulation of macrophage TLRs by bacterial products activates NFκB which drives transcription of interleukin-12, along with other cytokines and chemokines that subsequently recruit and instruct T cells. Secreted IL-12 stimulates T cells to produce IFNγ, which serves to further stimulate the macrophage. Activation of macrophages by IFNγ leads to induction of transcription factors such as STAT1 and CBP, which facilitate production of transactivators, including CIITA. This results in the transcription of multiple IFNγ-regulated genes, including MHCII, CD86, and CD64. MHCII is required for antigen presentation and, along with CD86, is used by macrophages to activate CD4+ T-helper cells. Antibody-opsonized particles are recognized by the phagocytic receptor, CD64, which binds the Fc portion of IgG. TLR1 602I traffics to the cell surface where it forms heterodimers with TLR2 to sense microbial agonists. Binding of the mycobacterial 19 kDa lipoprotein to TLR1/2 has been shown to block STAT1-CBP activity, thereby dampening the induction of IFNγ-regulated genes. It is possible that the trafficking-deficient TLR1 602S allele (dashed lines) confers protection against leprosy and TB by preventing the subversion of IFNγ signaling by these mycobacterial agonists.