Characterization of Human CD8 T Cell Responses in Dengue Virus-Infected Patients from India.
Characterization of Human CD8 T Cell Responses in Dengue Virus-Infected Patients from India.
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DOI：
10.1128/jvi.01424-16
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发表时间：
2016-12-15
影响因子：
5.4
通讯作者：
Murali-Krishna K
中科院分区：
文献类型：
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作者：
Chandele A;Sewatanon J;Gunisetty S;Singla M;Onlamoon N;Akondy RS;Kissick HT;Nayak K;Reddy ES;Kalam H;Kumar D;Verma A;Panda H;Wang S;Angkasekwinai N;Pattanapanyasat K;Chokephaibulkit K;Medigeshi GR;Lodha R;Kabra S;Ahmed R;Murali-Krishna K
流行病学研究表明，印度是全世界登革热病毒感染病例最多的国家。然而，关于这些患者的免疫反应的信息很少。CD8 T细胞在登革热中很重要，因为它们在保护和免疫病理中都有作用。在这里，我们提供了来自印度和泰国登革热患者的HLA-DR+ CD38+和HLA-DR - CD38+效应CD8 T细胞亚群的详细分析。两种CD8 T细胞亚群均扩增并表达抗原驱动增殖、组织归巢和细胞毒性效应功能的标志物，其中HLA-DR+ CD38+亚群在这些效应特性中最为显著。登革热特异性CD8 T细胞应答的广度是多种多样的，其中ns3特异性细胞是最主要的。有趣的是，当受登革病毒肽池刺激时，只有一小部分活化的CD8 T细胞产生γ干扰素（IFN-γ）。转录组学揭示了参与T细胞受体（TCR）信号传导的关键分子的下调。与此一致的是，即使在tcr依赖性多克隆刺激（抗cd3 +抗cd28）后，大多数CD8 T细胞仍对IFN-γ无反应，但通过tcr非依赖性多克隆刺激（phorbol 12-肉豆蔻酸13-乙酸酯[PMA] +离子霉素）产生IFN-γ。因此，绝大多数这些增殖的，高度分化的效应CD8 T细胞可能在患者经历导致IFN-γ无反应的发热性疾病时获得TCR难治性。我们的研究为理解CD8 T细胞介导的登革热保护作用与病理作用之间的平衡机制开辟了新的途径。登革热正在成为一个全球性的公共卫生问题。尽管CD8 T细胞在登革热的保护和细胞因子介导的免疫病理中都有牵连，但如何维持这些相反功能之间的平衡仍不清楚。我们全面表征了印度和泰国登革热患者的CD8 T细胞亚群，并表明这些细胞大量扩增并表达表型，表明压倒性的抗原刺激和组织归巢/细胞毒性效应功能，但绝大多数细胞在体外不能产生IFN-γ。有趣的是，当以T细胞受体（TCR）独立的方式刺激时，细胞完全能够产生细胞因子，但在TCR依赖的刺激下却不能。这些结果与转录组学一起揭示了来自登革热患者的绝大多数CD8 T细胞由于TCR信号传导不足而变得细胞因子无反应。这些观察结果为理解调节cd8介导的保护作用与病理作用之间的平衡机制开辟了新的途径。
Epidemiological studies suggest that India has the largest number of dengue virus infection cases worldwide. However, there is minimal information about the immunological responses in these patients. CD8 T cells are important in dengue, because they have been implicated in both protection and immunopathology. Here, we provide a detailed analysis of HLA-DR+ CD38+ and HLA-DR− CD38+ effector CD8 T cell subsets in dengue patients from India and Thailand. Both CD8 T cell subsets expanded and expressed markers indicative of antigen-driven proliferation, tissue homing, and cytotoxic effector functions, with the HLA-DR+ CD38+ subset being the most striking in these effector qualities. The breadth of the dengue-specific CD8 T cell response was diverse, with NS3-specific cells being the most dominant. Interestingly, only a small fraction of these activated effector CD8 T cells produced gamma interferon (IFN-γ) when stimulated with dengue virus peptide pools. Transcriptomics revealed downregulation of key molecules involved in T cell receptor (TCR) signaling. Consistent with this, the majority of these CD8 T cells remained IFN-γ unresponsive even after TCR-dependent polyclonal stimulation (anti-CD3 plus anti-CD28) but produced IFN-γ by TCR-independent polyclonal stimulation (phorbol 12-myristate 13-acetate [PMA] plus ionomycin). Thus, the vast majority of these proliferating, highly differentiated effector CD8 T cells probably acquire TCR refractoriness at the time the patient is experiencing febrile illness that leads to IFN-γ unresponsiveness. Our studies open novel avenues for understanding the mechanisms that fine-tune the balance between CD8 T cell-mediated protective versus pathological effects in dengue. IMPORTANCE Dengue is becoming a global public health concern. Although CD8 T cells have been implicated both in protection and in the cytokine-mediated immunopathology of dengue, how the balance is maintained between these opposing functions remains unknown. We comprehensively characterized CD8 T cell subsets in dengue patients from India and Thailand and show that these cells expand massively and express phenotypes indicative of overwhelming antigenic stimulus and tissue homing/cytotoxic-effector functions but that a vast majority of them fail to produce IFN-γ in vitro. Interestingly, the cells were fully capable of producing the cytokine when stimulated in a T cell receptor (TCR)-independent manner but failed to do so in TCR-dependent stimulation. These results, together with transcriptomics, revealed that the vast majority of these CD8 T cells from dengue patients become cytokine unresponsive due to TCR signaling insufficiencies. These observations open novel avenues for understanding the mechanisms that fine-tune the balance between CD8-mediated protective versus pathological effects.