A natural polymorphism of Mycobacterium tuberculosis in the esxH gene disrupts immunodomination by the TB10.4-specific CD8 T cell response.
A natural polymorphism of Mycobacterium tuberculosis in the esxH gene disrupts immunodomination by the TB10.4-specific CD8 T cell response.
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结核分枝杆菌 esxH 基因中的天然多态性会破坏 TB10.4 特异性 CD8 T 细胞反应的免疫支配作用。
DOI：
10.1371/journal.ppat.1009000
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发表时间：
2020-10
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：
Sutiwisesak R;Hicks ND;Boyce S;Murphy KC;Papavinasasundaram K;Carpenter SM;Boucau J;Joshi N;Le Gall S;Fortune SM;Sassetti CM;Behar SM
CD8 T 细胞在小鼠模型中对结核分枝杆菌 (Mtb) 感染提供有限的保护。由于 Mtb 会导致小鼠和人类慢性感染，因此我们假设 Mtb 会损害 T 细胞反应，作为一种免疫逃避策略。 TB10.4 是人类、非人灵长类动物和小鼠的免疫显性抗原，由 esxH 基因编码。在 C57BL/6 小鼠中，30–50% 的肺部 CD8 T 细胞识别 TB10.44−11 表位。然而，TB10.4 特异性 CD8 T 细胞无法识别 Mtb 感染的巨噬细胞。我们推测 Mtb 会引发对受感染细胞低效呈递的抗原的免疫显性 CD8 T 细胞反应，从而将 CD8 T 细胞集中在非保护性抗原上。在这里，我们利用 esxH 中自然发生的多态性（这种多态性经常出现在谱系 1 菌株中）来测试这种“诱饵假设”。使用含有 EsxHA10T 多态性的临床分离株 667，我们观察到 CD8 T 细胞层次结构的巨大变化。使用同基因 Erd.EsxHA10T 和 Erd.EsxHWT 菌株，我们证明这种多态性改变了免疫显性 CD8 T 细胞反应的层次结构。我们的数据最好用免疫支配来解释，免疫支配是一种机制，通过这种机制，APC 的竞争导致显性反应抑制次显性反应。这些结果令人惊讶，因为变异表位可以与 H2-Kb 结合并被 TB10.4 特异性 CD8 T 细胞识别。 TB10.4 特异性 CD8 反应的巨大变化是由于 A10T 变体的蛋白水解降解增加导致的，这破坏了 TB10.44-11 表位。重要的是，这种多态性影响了 T 细胞的启动和对感染细胞的识别。这些数据支持一种模型，其中非保护性 CD8 T 细胞成为免疫优势并抑制次优势反应。因此，临床 Mtb 菌株与基于 BCG 或 H37Rv 序列的疫苗之间的多态性可能导致疫苗引发的 T 细胞与受感染细胞呈现的表位之间不匹配。在未来的疫苗设计中应考虑重新编程宿主免疫反应。对于疫苗开发人员来说，一个重要的问题是 CD4 与 CD8 T 细胞对抗 Mtb 的相对效力，因为引发这些不同 T 细胞亚群的策略不同。尽管抗原特异性肺部 CD8 T 细胞反应强烈，但在小鼠模型中，CD4 T 细胞比 CD8 T 细胞介导更多的保护作用。大多数 CD8 T 细胞识别单一抗原 TB10.4，该抗原由 esxH 基因编码。基于发现 TB10.44−11 特异性 CD8 T 细胞很难识别 Mtb 感染的巨噬细胞，我们假设 Mtb 逃避 CD8 T 细胞的检测，并将 CD8 T 细胞反应集中在非保护性抗原上。我们将这些抗原称为“诱饵抗原”。为了检验这一假设，我们利用了 esxH 基因的天然变体，该变体在 TB10.44−11 表位内包含 A10T 多态性。这种多态性极大地改变了 Mtb 引起的 CD8 T 细胞反应的层次结构。这些数据表明，TB10.4表位的免疫支配作用可抑制亚优势CD8 T细胞对其他Mtb抗原的反应，损害CD8 T细胞对其他Mtb抗原的反应，其中一些抗原可能由Mtb感染的巨噬细胞呈递并成为保护性免疫的目标。重要的是，这种单一氨基酸多态性不会显着改变 MHC 结合或 T 细胞识别，但会改变表位的半衰期，因此对 CD8 T 细胞启动和感染细胞的识别产生深远影响。这些数据还提供了一种可用于操纵免疫显性反应层次的机制。
CD8 T cells provide limited protection against Mycobacterium tuberculosis (Mtb) infection in the mouse model. As Mtb causes chronic infection in mice and humans, we hypothesize that Mtb impairs T cell responses as an immune evasion strategy. TB10.4 is an immunodominant antigen in people, nonhuman primates, and mice, which is encoded by the esxH gene. In C57BL/6 mice, 30–50% of pulmonary CD8 T cells recognize the TB10.44−11 epitope. However, TB10.4-specific CD8 T cells fail to recognize Mtb-infected macrophages. We speculate that Mtb elicits immunodominant CD8 T cell responses to antigens that are inefficiently presented by infected cells, thereby focusing CD8 T cells on nonprotective antigens. Here, we leverage naturally occurring polymorphisms in esxH, which frequently occur in lineage 1 strains, to test this “decoy hypothesis”. Using the clinical isolate 667, which contains an EsxHA10T polymorphism, we observe a drastic change in the hierarchy of CD8 T cells. Using isogenic Erd.EsxHA10T and Erd.EsxHWT strains, we prove that this polymorphism alters the hierarchy of immunodominant CD8 T cell responses. Our data are best explained by immunodomination, a mechanism by which competition for APC leads to dominant responses suppressing subdominant responses. These results were surprising as the variant epitope can bind to H2-Kb and is recognized by TB10.4-specific CD8 T cells. The dramatic change in TB10.4-specific CD8 responses resulted from increased proteolytic degradation of A10T variant, which destroyed the TB10.44-11epitope. Importantly, this polymorphism affected T cell priming and recognition of infected cells. These data support a model in which nonprotective CD8 T cells become immunodominant and suppress subdominant responses. Thus, polymorphisms between clinical Mtb strains, and BCG or H37Rv sequence-based vaccines could lead to a mismatch between T cells that are primed by vaccines and the epitopes presented by infected cells. Reprograming host immune responses should be considered in the future design of vaccines. An important question for vaccine developers is the relative potency of CD4 vs. CD8 T cells against Mtb, as strategies differ for eliciting these different T cell subsets. Despite robust antigen-specific pulmonary CD8 T cell responses, CD4 T cells mediate more protection than CD8 T cells in the murine model. Most CD8 T cells recognize a single antigen, TB10.4, which is encoded by the esxH gene. Based on finding that TB10.44−11-specific CD8 T cells poorly recognize Mtb-infected macrophages, we hypothesized that Mtb evades detection by CD8 T cells and focuses the CD8 T cell response on non-protective antigen. We termed these antigens “decoy antigens.” To test this hypothesis, we took advantage of a natural variant of the esxH gene, which contains an A10T polymorphism within the TB10.44−11 epitope. This polymorphism drastically alters the hierarchy of CD8 T cell responses elicited by Mtb. These data suggest that immunodomination by the TB10.4 epitope acts to suppress subdominant CD8 T cell responses to other Mtb antigens, impairing the CD8 T cell response to other Mtb antigens, some of which might be presented by Mtb-infected macrophages and be targets of protective immunity. Importantly, this single amino acid polymorphism, which does not significantly alter MHC-binding or T cell recognition, alters the half-life of the epitope and consequently, has a profound effect on CD8 T cell priming and recognition of infected cells. These data also provide a mechanism that could be exploited to manipulate the hierarchy of immunodominant responses.
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影响因子：
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