Abstract
CD4 Tcells 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 Tcells have conferred little or no protection. Here we examined CD4 Tcell 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 Tcells to be more differentiated than Ag85B-specific Tcells. The ability of each Tcell population to control Mtb in the lungs of mice was restricted for opposite reasons: Ag85B-specific Tcells were limited by reduced antigen expression during persistent infection, whereas ESAT-6-specific Tcells became functionally exhausted due to chronic antigenic stimulation. Our findings suggest that different vaccination strategies will be required tooptimize protection mediated by Tcells recognizing antigens expressed at distinct stages of Mtb infection.
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