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Moguche, Albanus O.; Musvosvi, Munyaradzi; Penn-Nicholson, Adam; Plumlee, Courtney R.; Mearns, Helen; Geldenhuys, Hennie; Smit, Erica; Abrahams, Deborah; Rozot, Virginie; Dintwe, One; Hoff, Søren T.; Kromann, Ingrid; Ruhwald, Morten; Bang, Peter; Larson, Ryan P.; Shafiani, Shahin; Ma, Shuyi; Sherman, David R.; Sette, Alessandro; Lindestam Arlehamn, Cecilia S.; McKinney, Denise M.; Maecker, Holden; Hanekom, Willem A.; Hatherill, Mark; Andersen, Peter; Scriba, Thomas J.; Urdahl, Kevin B.
Cell host & microbe, 06/2017, Letnik: 21, Številka: 6Journal Article
CD4 T cells are critical for protective immunity against Mycobacterium tuberculosis (Mtb), the cause of tuberculosis (TB). Yet to date, TB vaccine candidates that boost antigen-specific CD4 T cells have conferred little or no protection. Here we examined CD4 T cell responses to two leading TB vaccine antigens, ESAT-6 and Ag85B, in Mtb-infected mice and in vaccinated humans with and without underlying Mtb infection. In both species, Mtb infection drove ESAT-6-specific T cells to be more differentiated than Ag85B-specific T cells. The ability of each T cell population to control Mtb in the lungs of mice was restricted for opposite reasons: Ag85B-specific T cells were limited by reduced antigen expression during persistent infection, whereas ESAT-6-specific T cells became functionally exhausted due to chronic antigenic stimulation. Our findings suggest that different vaccination strategies will be required to optimize protection mediated by T cells recognizing antigens expressed at distinct stages of Mtb infection. Display omitted •Mtb antigen Ag85B-specific CD4 T cells maintain memory cell features during infection•Antigen availability limits immunity conferred by Ag85B-specific CD4 T cells•Mtb antigen ESAT-6-specific CD4 T cells are driven toward terminal differentiation•Functional exhaustion restricts ESAT-6-specific CD4 T cell-mediated immunity against Mtb Moguche and Musvosvi et al. show that two leading Mycobacterium tuberculosis vaccine antigens, Ag85B and ESAT-6, are differentially expressed during infection. As a result, CD4 T cells recognizing these antigens exhibit distinct patterns of differentiation, and their capacities to mediate protective immunity are restricted in different ways.
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