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.

CD4 T细胞对于抵抗结核分枝杆菌（TB）的结核分枝杆菌（Mtb）的保护性免疫至关重要。迄今为止，增强抗原特异性CD4 T细胞的TB疫苗候选者几乎没有保护，甚至没有保护。在这里，我们研究了在Mtb感染的小鼠和有无Mtb感染的人中，CD4 T细胞对两种主要的TB疫苗抗原ESAT-6和Ag85B的反应。在这两个物种中，Mtb感染驱使ESAT-6特异性T细胞比Ag85B特异性T细胞分化更高。每个T细胞群控制小鼠肺中Mtb的能力由于相反的原因而受到限制：Ag85B特异性T细胞受到持续感染过程中抗原表达降低的限制，而ESAT-6特异性T细胞由于慢性感染而功能衰竭抗原刺激。