Suboptimal activation of antigen-specific cD4+ effector cells enables persistence of M. tuberculosis in vivo

Adaptive immunity to mycobacterium tuberculosis controls progressive bacterial growth and disease but does not eradicate infection. among cd4+ t cells in the lungs of m. tuberculosis-infected mice,we observed that few produced ifn-γ without ex vivo restimulation. therefore,we hypothesized that one mechanism whereby m. tuberculosis avoids elimination is by limiting activation of cd4+ effector t cells at the site of infection in the lungs. to test this hypothesis,we adoptively transferred th1-polarized cd4+ effector t cells specific for m. tuberculosis ag85b peptide 25 (p25tcrth1 cells),which trafficked to the lungs of infected mice and exhibited antigen-dependent ifn-γ production. during the early phase of infection,~10% of p25tcrth1 cells produced ifn-γ in vivo; this declined to <1% as infection progressed to chronic phase. bacterial downregulation of fbpb (encoding ag85b) contributed to the decrease in effector t cell activation in the lungs,as a strain of m. tuberculosis engineered to express fbpb in the chronic phase stimulated p25tcrth1 effector cells at higher frequencies in vivo,and this resulted in cd4+ t cell-dependent reduction of lung bacterial burdens and prolonged survival of mice. administration of synthetic peptide 25 alone also increased activation of endogenous antigen-specific effector cells and reduced the bacterial burden in the lungs without apparent host toxicity. these results indicate that cd4+ effector t cells are activated at suboptimal frequencies in tuberculosis,and that increasing effector t cell activation in the lungs by providing one or more epitope peptides may be a successful strategy for tb therapy. © 2011 bold et al.