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Vaccine-induced anti-tuberculosis protective immunity in mice correlates with the magnitude and quality of multifunctional CD4 T cells

Laboratory of Mycobacterial Diseases and Cellular Immunology, Center for Biologics Evaluation and Research, United States Food and Drug Administration, Bethesda, MD 20892, United States.
Vaccine (Impact Factor: 3.49). 02/2011; 29(16):2902-9. DOI: 10.1016/j.vaccine.2011.02.010
Source: PubMed

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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    • "However, in most of these studies, the frequency of specific cytokine (IFN-γ) secreting T cells was typically used as the parameter to measure the specific T cell responses. But this might not be the best indicator of protective T cell responses, because several lines of evidence have already suggested that the mean fluorescent intensity (MFI) also was an important coparameter [12] [13] [14]. In order to further improve the immunogenicity of epitope-based DNA vaccine, in this study, we constructed epitope-based DNA vaccines by using a combined immunogenicity-enhancing design. "
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    • "It should be noted that IFN-␥ expression alone is not always indicative of protection against E. ruminantium infection in vivo (Vachiéry et al., 2006). Recent studies on protective immunity against Mycobacterium tuberculosis have shown a better correlation between protection and the number of multifunctional T (MFT) cells which were detected in immune pulmonary and spleen cell preparations (Derrick et al., 2011). MFT cells are single cells that produce high concentrations of the cytokines IFN-␥; TNF-␣ and IL-2. "
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