Vaccine-induced anti-tuberculosis protective immunity in mice correlates with the magnitude and quality of multifunctional CD4 T cells.
ABSTRACT The development of improved vaccines against Mycobacterium tuberculosis has been hindered by a limited understanding of the immune correlates of anti-tuberculosis protective immunity. In this study, we examined the relationship between long-term anti-tuberculosis protection and the mycobacterial-specific CD4 multifunctional T (MFT) cell responses induced by five different TB vaccines (live-attenuated, subunit, viral vectored, plasmid DNA, and combination vaccines) in a mouse model of pulmonary tuberculosis. In a 14-month experiment, we showed that TB vaccine-induced CD4 T cell responses were heterogenous. Antigen-specific monofunctional CD4 T cells expressing single cytokines and MFT CD4 T cells expressing multiple cytokines (IFN-γ and TNF-α, IFN-γ and IFN-γ, TNF-α, and IL-2, and all three cytokines) were identified after the immunizations. Interestingly, compared to the monofunctional cells, significantly higher median fluorescent intensities (MFIs) for IFN-γ and TNF-α were detected for triple-positive MFT CD4 T cells induced by the most protective vaccines while modest differences in relative MFI values were seen for the less protective preparations. Most importantly during the 14-month study, the levels of vaccine-induced pulmonary and splenic protective immunity correlated with the frequency and the integrated MFI (iMFI, frequency×MFI) values of triple-positive CD4 T cells that were induced by the same vaccines. These data support efforts to use MFT cell analyses as a measure of TB vaccine immunogenicity in human immunization studies.
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ABSTRACT: Abstract Effective vaccination against intracellular pathogens, such as tuberculosis (TB), relies on the generation and maintenance of CD4 memory T cells. An incomplete understanding of the memory immune response has hindered the rational design of a new, more effective TB vaccine. This review discusses how the persistence of antigen, the location of memory cells, and their multifunctional ability shape the CD4 memory T cell response against TB.Biomolecular concepts 02/2012; 3(1):13-20. DOI:10.1515/bmc.2011.051
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ABSTRACT: Tuberculosis remains a global health problem, in part due to failure of the currently available vaccine, BCG, to protect adults against pulmonary forms of the disease. We explored the impact of pulmonary delivery of recombinant influenza A viruses (rIAV) on the induction of Mycobacterium tuberculosis-specific CD4(+) and CD8(+) T-cell responses and the resultant protection against M. tuberculosis infection in C57BL/6 mice. Intranasal infection with rIAVs expressing a CD4(+) T cell epitope from the Ag85B protein (PR8.p25) or CD8(+) T cell epitope from the TB10.4 protein (PR8.TB10.4) generated strong T cell responses to the M. tuberculosis-specific epitopes in the lung that persisted long after the rIAVs were cleared. Infection with PR8.p25 conferred protection against subsequent M. tuberculosis challenge in the lung, and this was associated with increased levels of poly-functional CD4(+) T cells at the time of challenge. By contrast, infection with PR8.TB10.4 did not induce protection despite the presence of IFN-γ-producing M. tuberculosis-specific CD8(+) T cells in the lung at the time of challenge and during infection. Therefore, the induction of pulmonary M. tuberculosis epitope-specific CD4(+) , but not CD8(+) T cells, is essential for protection against acute M. tuberculosis infection in the lung. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.European Journal of Immunology 03/2015; 45(3). DOI:10.1002/eji.201444954 · 4.52 Impact Factor
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ABSTRACT: Cytokines, because of their nature of soluble mediators, represent key elements in mediating and tuning the immune response against Mycobacterium tuberculosis.•Mycobacterium tuberculosis orchestrates the cytokine storm to induce or evade host immune responses.•Granuloma formation is tightly regulated by lung-secreted cytokines.•Perturbation of cytokine signaling represents a critical checkpoint of the immune response against Mycobacterium tuberculosis.•Understanding the balance between pro- and anti-inflammatory cytokines is crucial for developing more effective measures of immune intervention against tuberculosis.Seminars in Immunology 11/2014; 26(6). DOI:10.1016/j.smim.2014.09.011 · 6.12 Impact Factor