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

摘要

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 effectorcells at higher frequencies in vivo, and this resulted in CD4⁺ Tcell-dependent reduction of lung bacterial burdens and prolonged survival ofmice. Administration of synthetic peptide 25 alone also increased activation ofendogenous antigen-specific effector cells and reduced the bacterial burden inthe lungs without apparent host toxicity. These results indicate thatCD4⁺ effector T cells are activated at suboptimalfrequencies in tuberculosis, and that increasing effector T cell activation inthe lungs by providing one or more epitope peptides may be a successful strategyfor TB therapy.