早期 T 滤泡辅助细胞反应和生发中心反应与免疫恒河猴的病毒血症控制相关。
Early T Follicular Helper Cell Responses and Germinal Center Reactions Are Associated with Viremia Control in Immunized Rhesus Macaques.
机构信息
Immune Biology of Retroviral Infection Section, Vaccine Branch, NCI, NIH, Bethesda, Maryland, USA.
Biostatistics and Data Management Section, NCI, NIH, Bethesda, Maryland, USA.
出版信息
J Virol. 2019 Feb 5;93(4). doi: 10.1128/JVI.01687-18. Print 2019 Feb 15.
T follicular helper (T) cells are fundamental in germinal center (GC) maturation and selection of antigen-specific B cells within secondary lymphoid organs. GC-resident T cells have been fully characterized in human immunodeficiency virus (HIV) infection. However, the role of GC T cells in GC B cell responses following various simian immunodeficiency virus (SIV) vaccine regimens in rhesus macaques (RMs) has not been fully investigated. We characterized GC T cells of RMs over the course of a mucosal/systemic vaccination regimen to elucidate GC formation and SIV humoral response generation. Animals were mucosally primed twice with replicating adenovirus type 5 host range mutant (Ad5hr)-SIV recombinants and systemically boosted with ALVAC-SIVGag/Pro/gp120-TM and SIV gD-gp120 proteins formulated in alum hydroxide (ALVAC/Env) or DNA encoding SIVenv/SIVGag/rhesus interleukin 12 (IL-12) plus SIV gD-gp120 proteins formulated in alum phosphate (DNA&Env). Lymph nodes were biopsied in macaque subgroups prevaccination and at day 3, 7, or 14 after the 2nd Ad5hr-SIV prime and the 2nd vector/Env boost. Evaluations of GC T and GC B cell dynamics including correlation analyses supported a significant role for early GC T cells in providing B cell help during initial phases of GC formation. GC T responses at day 3 post-mucosal priming were consistent with generation of Env-specific memory B cells in GCs and elicitation of prolonged Env-specific humoral immunity in the rectal mucosa. GC Env-specific memory B cell responses elicited early post-systemic boosting correlated significantly with decreased viremia postinfection. Our results highlight the importance of early GC T cell responses for robust GC maturation and generation of long-lasting SIV-specific humoral responses at mucosal and systemic sites. Further investigation of GC T cell dynamics should facilitate development of an efficacious HIV vaccine. The modest HIV protection observed in the human RV144 vaccine trial associated antibody responses with vaccine efficacy. T follicular helper (T) cells are CD4 T cells that select antibody secreting cells with high antigenic affinity in germinal centers (GCs) within secondary lymphoid organs. To evaluate the role of T cells in eliciting prolonged virus-specific humoral responses, we vaccinated rhesus macaques with a combined mucosal prime/systemic boost regimen followed by repeated low-dose intrarectal challenges with SIV, mimicking human exposure to HIV-1. Although the vaccine regimen did not prevent SIV infection, decreased viremia was observed in the immunized macaques. Importantly, vaccine-induced T responses elicited at day 3 postimmunization and robust GC maturation were strongly associated. Further, early T-dependent SIV-specific B cell responses were also correlated with decreased viremia. Our findings highlight the contribution of early vaccine-induced GC T responses to elicitation of SIV-specific humoral immunity and implicate their participation in SIV control.
滤泡辅助 T 细胞(Tfh)在生发中心(GC)成熟和次级淋巴器官中抗原特异性 B 细胞的选择中起关键作用。GC 驻留 T 细胞在人类免疫缺陷病毒(HIV)感染中已得到充分描述。然而,在恒河猴(RMs)中,各种猴免疫缺陷病毒(SIV)疫苗方案中,GC T 细胞在 GC B 细胞反应中的作用尚未得到充分研究。我们在粘膜/系统疫苗接种方案过程中对 RMs 的 GC T 细胞进行了表征,以阐明 GC 的形成和 SIV 体液反应的产生。动物通过两次粘膜初免复制腺病毒 5 型宿主范围突变(Ad5hr)-SIV 重组体,并通过 ALVAC-SIVGag/Pro/gp120-TM 和 SIV gD-gp120 蛋白进行系统加强,这些蛋白以氢氧化铝(ALVAC/Env)或编码 SIVenv/SIVGag/rhesus 白细胞介素 12(IL-12)的 DNA 以及 SIV gD-gp120 蛋白的形式配制在磷酸铝(DNA&Env)中。在第二次 Ad5hr-SIV 初免和第二次载体/Env 加强后的第 2 天、第 3 天、第 7 天或第 14 天,对猕猴亚组的淋巴结进行活检。对 GC T 和 GC B 细胞动力学的评估,包括相关性分析,支持早期 GC T 细胞在 GC 形成的初始阶段为 B 细胞提供帮助的重要作用。粘膜初免后第 3 天的 GC T 反应与 GC 中 Env 特异性记忆 B 细胞的产生以及直肠粘膜中延长的 Env 特异性体液免疫的产生一致。早期系统加强后 GC Env 特异性记忆 B 细胞反应与感染后病毒载量降低显著相关。我们的结果强调了早期 GC T 细胞反应对于在粘膜和全身部位产生强大的 GC 成熟和持久的 SIV 特异性体液反应的重要性。进一步研究 GC T 细胞动力学应有助于开发有效的 HIV 疫苗。人类 RV144 疫苗试验中观察到的适度 HIV 保护作用与疫苗功效相关联的抗体反应。滤泡辅助 T(Tfh)细胞是 CD4 T 细胞,在次级淋巴器官的生发中心(GC)中选择具有高抗原亲和力的抗体分泌细胞。为了评估 T 细胞在引发延长的病毒特异性体液反应中的作用,我们用粘膜初免/系统加强方案对恒河猴进行了疫苗接种,然后用 SIV 重复进行低剂量直肠内挑战,模拟人类接触 HIV-1。虽然疫苗方案不能预防 SIV 感染,但免疫猕猴的病毒载量降低。重要的是,疫苗接种后第 3 天诱导的 T 反应与强烈相关。此外,早期依赖 T 的 SIV 特异性 B 细胞反应也与病毒载量降低相关。我们的发现强调了早期疫苗诱导的 GC T 反应对 SIV 特异性体液免疫的激发作用,并表明它们参与了 SIV 的控制。
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