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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.

Suboptimal Activation of Antigen-Specific CD4+ Effector Cells Enables Persistence of M. tuberculosis In Vivo