15 research outputs found
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
The ubiquitin ligase parkin mediates resistance to intracellular pathogens
Ubiquitin-mediated targeting of intracellular bacteria to the autophagy pathway is a key innate defence mechanism against invading microbes, including the important human pathogen Mycobacterium tuberculosis. However, the ubiquitin ligases responsible for