A Higher Activation Threshold of Memory CD8+ T Cells Has a Fitness Cost That Is Modified by TCR Affinity during Tuberculosis.
A Higher Activation Threshold of Memory CD8+ T Cells Has a Fitness Cost That Is Modified by TCR Affinity during Tuberculosis.
复制标题
记忆CD8+ T细胞的更高活化阈值具有结核病期间TCR亲和力改变的适应性成本。
DOI：
10.1371/journal.ppat.1005380
复制
发表时间：
2016-01
期刊：
影响因子：
6.7
通讯作者：
Behar SM
中科院分区：
文献类型：
--
作者：
Carpenter SM;Nunes-Alves C;Booty MG;Way SS;Behar SM
针对结核分枝杆菌（Mtb）和其他病原体的T细胞疫苗的原理是，记忆T细胞在受到攻击后迅速产生效应反应，从而清除病原体。尽管免疫优势型Mtb抗原TB10.4 （EsxH）诱导了强大的记忆性CD8+ T细胞应答，但我们发现接种TB10.4特异性CD8+ T细胞的频率增加在Mtb攻击后是短暂的。为了比较记忆和naïve CD8+ T细胞在Mtb应答过程中的功能，我们使用tb10.4特异性逆转录CD8+ T细胞追踪它们的扩增。我们发现，在Mtb挑战期间，主要（naïve）反应超过次要（记忆）反应，这种影响被TCR亲和力的增加所缓和。为了确定Mtb攻击后多克隆记忆T细胞的扩增是否受到抑制，我们使用TCRβ深度测序来追踪接种疫苗和随后攻击的完整小鼠tb10.4特异性CD8+ T细胞。成功的记忆T细胞，通过Mtb攻击后的克隆扩增来定义，表达类似的CDR3β序列，表明抗原选择了TCR。因此，tcr依赖性和非依赖性因素都会影响记忆CD8+反应的适应性。大多数记忆T细胞克隆型扩增受损可能解释了为什么一些结核病疫苗没有提供更好的保护。CD8+ T细胞对于加强结核病的潜伏期和控制艾滋病毒和低CD4计数患者的结核分枝杆菌很重要。虽然主要引起CD4+ T细胞反应的疫苗难以预防活动性肺结核，但引发有效记忆性CD8+ T细胞的结核病疫苗是一种合乎逻辑的替代策略。记忆T细胞被认为比原发T细胞（naïve）反应更快。然而，通过直接比较naïve和记忆TCR逆转录CD8+ T细胞在感染期间特异性TB10.4抗原，我们观察到记忆来源的T细胞比naïve-derived T细胞更不适合。我们将记忆性CD8+ T细胞适应性的降低与其对抗原敏感性的降低联系起来，并表明适应性可以通过增加TCR亲和力来改善。利用一种新的方法来追踪完整小鼠对Mtb气溶胶攻击反应期间接种疫苗引起的CD8+ T细胞，我们观察到新的初级反应的强劲扩展以及次要反应的克隆选择，可能是由TCR亲和力驱动的。我们提出产生具有高亲和力的记忆T细胞应该成为结核病疫苗的一个目标。
T cell vaccines against Mycobacterium tuberculosis (Mtb) and other pathogens are based on the principle that memory T cells rapidly generate effector responses upon challenge, leading to pathogen clearance. Despite eliciting a robust memory CD8+ T cell response to the immunodominant Mtb antigen TB10.4 (EsxH), we find the increased frequency of TB10.4-specific CD8+ T cells conferred by vaccination to be short-lived after Mtb challenge. To compare memory and naïve CD8+ T cell function during their response to Mtb, we track their expansions using TB10.4-specific retrogenic CD8+ T cells. We find that the primary (naïve) response outnumbers the secondary (memory) response during Mtb challenge, an effect moderated by increased TCR affinity. To determine whether the expansion of polyclonal memory T cells is restrained following Mtb challenge, we used TCRβ deep sequencing to track TB10.4-specific CD8+ T cells after vaccination and subsequent challenge in intact mice. Successful memory T cells, defined by their clonal expansion after Mtb challenge, express similar CDR3β sequences suggesting TCR selection by antigen. Thus, both TCR-dependent and -independent factors affect the fitness of memory CD8+ responses. The impaired expansion of the majority of memory T cell clonotypes may explain why some TB vaccines have not provided better protection. CD8+ T cells are important for enforcing latency of tuberculosis, and for Mtb control in patients with HIV and low CD4 counts. While vaccines that primarily elicit CD4+ T cell responses have had difficulty preventing active pulmonary TB, a TB vaccine that elicits a potent memory CD8+ T cells is a logical alternative strategy. Memory T cells are thought to respond more rapidly than the primary (naïve) response. However, by directly comparing naïve and memory TCR retrogenic CD8+ T cells specific for the TB10.4 antigen during infection, we observe memory-derived T cells to be less fit than naïve-derived T cells. We relate the reduced fitness of memory CD8+ T cells to their lower sensitivity to antigen and show that fitness can be improved by increasing TCR affinity. Using a novel method for tracking CD8+ T cells elicited by vaccination during the response to Mtb aerosol challenge in intact mice, we observe the robust expansion of a new primary response as well as clonal selection of the secondary response, likely driven by TCR affinity. We propose that generating memory T cells with high affinities should be a goal of vaccination against TB.