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

TD Bold, N Banaei, AJ Wolf, JD Ernst - PLoS pathogens, 2011 - journals.plos.org
TD Bold, N Banaei, AJ Wolf, JD Ernst
PLoS pathogens, 2011journals.plos.org
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 …
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.
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