title: Suboptimal activation of antigen-specific CD4+ effector cells enables persistence of M. tuberculosis in vivo.
abstract: 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.
authors.affiliation: Department of Pathology, New York University School of Medicine, New York City, New York, United States of America.
authors.forename: Tyler D
authors.initials: TD
authors.lastname: Bold
authors.forename: Niaz
authors.initials: N
authors.lastname: Banaei
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Wolf
authors.forename: Joel D
authors.initials: JD
authors.lastname: Ernst
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology*; D049109:Cell Proliferation; D004195:Disease Models, Animal; D007371:Interferon-gamma / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D050296:Microbial Viability; D009169:Mycobacterium tuberculosis / Q000276:immunology / Q000472:pathogenicity* / Q000502:physiology; D014376:Tuberculosis / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology*
chemical_list: D000942:Antigens, Bacterial; D015704:CD4 Antigens; D007371:Interferon-gamma