Division of Experimental Virology, Department of Biomedicine, University of Basel, 4003 Basel, Switzerland.
Immune Cell Biology Laboratory, Department of Biomedicine, University Hospital Basel, 4031 Basel, Switzerland.
Proc Natl Acad Sci U S A. 2021 Nov 16;118(46). doi: 10.1073/pnas.2108157118.
Chronic viral infections subvert protective B cell immunity. An early type I interferon (IFN-I)-driven bias to short-lived plasmablast differentiation leads to clonal deletion, so-called "decimation," of antiviral memory B cells. Therefore, prophylactic countermeasures against decimation remain an unmet need. We show that vaccination-induced CD4 T cells prevented the decimation of naïve and memory B cells in chronically lymphocytic choriomeningitis virus (LCMV)-infected mice. Although these B cell responses were largely T independent when IFN-I was blocked, preexisting T help assured their sustainability under conditions of IFN-I-driven inflammation by instructing a germinal center B cell transcriptional program. Prevention of decimation depended on T cell-intrinsic Bcl6 and Tfh progeny formation. Antigen presentation by B cells, interactions with antigen-specific T helper cells, and costimulation by CD40 and ICOS were also required. Importantly, B cell-mediated virus control averted Th1-driven immunopathology in LCMV-challenged animals with preexisting CD4 T cell immunity. Our findings show that vaccination-induced Tfh cells represent a cornerstone of effective B cell immunity to chronic virus challenge, pointing the way toward more effective B cell-based vaccination against persistent viral diseases.
慢性病毒感染颠覆了保护性 B 细胞免疫。早期的 I 型干扰素（IFN-I）驱动的偏向短暂的浆母细胞分化导致抗病毒记忆 B 细胞的克隆性缺失，即所谓的“耗竭”。因此，预防耗竭仍然是一个未满足的需求。我们表明，疫苗接种诱导的 CD4 T 细胞可防止慢性淋巴细胞性脉络丛脑膜炎病毒（LCMV）感染小鼠中幼稚和记忆 B 细胞的耗竭。尽管在阻断 IFN-I 时，这些 B 细胞反应在很大程度上是 T 细胞非依赖性的，但预先存在的 T 辅助细胞通过指导生发中心 B 细胞转录程序，确保了它们在 IFN-I 驱动的炎症条件下的可持续性。预防耗竭取决于 T 细胞内在的 Bcl6 和 Tfh 前体形成。B 细胞的抗原呈递、与抗原特异性 T 辅助细胞的相互作用以及 CD40 和 ICOS 的共刺激也是必需的。重要的是，B 细胞介导的病毒控制避免了具有预先存在的 CD4 T 细胞免疫的 LCMV 挑战动物中的 Th1 驱动的免疫病理学。我们的研究结果表明，疫苗接种诱导的 Tfh 细胞是慢性病毒挑战中有效 B 细胞免疫的基石，为针对持续性病毒病的更有效的基于 B 细胞的疫苗接种指明了方向。
