Regulation of T-cell dependent B cell responses to influenza

 说明(申请人提供)：产生长寿命、高亲和力的抗体(Ab)是对大多数病毒的保护性免疫和疫苗接种后的保护所必需的。因此，了解控制产生长效保护性抗体反应的机制是至关重要的。T滤泡辅助性T细胞(TFH)是一种独特的CD4+T细胞亚群，高水平表达CXCR5，定位于B细胞滤泡，在促进长寿抗体应答中发挥重要作用。事实上，在没有TFH细胞的情况下，长期的抗体反应会受到损害，对病原体的保护也会受到影响。因此，我们必须了解如何操纵TFH反应，以提高疫苗的效力。然而，尽管该领域取得了重大进展，但我们对TFH细胞如何启动反应的了解非常有限。最近的研究表明，TFH细胞最初被启动 通过树突状细胞(DC)，这表明我们可能能够开发出优先激活DC以促进TFH细胞启动的佐剂，或者将疫苗抗原靶向于那些优先诱导TFH细胞的DC。不幸的是，我们不知道是什么信号引导DC促进TFH细胞分化，也不知道哪些特定的DC亚群启动了TFH细胞反应。因此，这项建议的长期目标是确定DC如何启动病毒特异性TFH细胞，这将帮助我们确定可用于增强TFH细胞反应的佐剂的性质。重要的是，尽管一些研究表明Tregs，特别是T滤泡调节(TFR)细胞抑制了Tfh和GC B细胞的反应，但我们最近发现Tregs促进了Tfh和B细胞对流感的反应。从机制上讲，Tregs通过限制IL-2的生理可用性而有利于流感特异性Tfh细胞的发展，IL-2是Tfh的有效抑制因子 细胞分化。因此，除了树突状细胞外，正常的TFH细胞反应也需要Tregs。将在这项提议中检验的中心假设是TFH细胞被启动 在T细胞区外的低IL-2微环境中，“促Tfh树突状细胞”(提供“促Tfh”信号)和Tregs(消耗IL-2)之间的协调相遇允许Tfh细胞分化。为了验证这一假设，在目标1中，我们将首先确定启动Tfh细胞反应所需的特定DC亚群和DC的激活状态，以及DC/Tregs/IL-2相互作用调节这一过程的分子机制。在目标2中，我们将确定趋化因子-趋化因子受体的相互作用，它协调了“前Tfh DC”和Tregs在T细胞区外的相遇。在目标3中，我们将确定IL-2和其他因素是如何控制TFR(抑制Tfh细胞反应)的发展的，这样我们就可以防止接种后TFR的分化。我们相信，我们的工作将大大有助于我们理解TFH细胞的反应是如何启动的，并揭示新的策略，以激发对感染和疫苗的长期抗体反应。这一建议是创新的，因为它专注于以前被忽视但却非常重要的TFH细胞生物学方面。

 DESCRIPTION (provided by applicant): The generation of long-lived, high affinity antibodies (Ab) is required for protective immunity to most viruses and for protection after vaccination. Thus, it is essential to understand the mechanisms that control the generation of long-lasting protective Ab responses. T follicular helper (Tfh) cells, a distinct CD4+ T cell subset that expresses high levels of CXCR5 and localizes in the B cell follicles, play an essential role on promoting long-lived Ab responses. In fact, in the absence of Tfh cells, long-term Ab responses are impaired and protection to pathogens compromised. Therefore, it is essential that we understand how to manipulate Tfh responses in order to improve the efficacy of vaccines. However, despite significant advances in the field, our understanding of how Tfh cells responses are initiated is very limited. Recent studies suggest that Tfh cells are initially primed by dendritic cells (DCs), suggesting that we may be able to develop adjuvants that preferentially activate DCs to promote Tfh cell priming, or target vaccine antigens to those DCs that preferentially induce Tfh cells. Unfortunately, we do not know what signals direct the DCs to promote Tfh cell differentiation or which specific subsets of DCs prime Tfh cell responses. Thus, the long-term goal of this proposal is to determine how virus-specific Tfh cells are primed by DCs, which will help us to determine the nature of adjuvants that can be used to boost Tfh cell responses. Importantly, whereas some studies suggest that Tregs, particularly the T follicular regulatory (TFR) cells, suppress Tfh and GC B cell responses, we recently found that Tregs promote Tfh and B cell responses to influenza. Mechanistically, Tregs favored influenza-specific Tfh cell development by limiting the physiological availability of IL-2, a potent suppressor of Tfh cell differentiation. Thus, in addition to DCs, Tregs are also required for normal Tfh cell responses. The central hypothesis that will be tested in this proposal is that Tfh cells are primed within particular low-IL-2 microenvironments outside the T cell area, where coordinated encounters between "pro-Tfh DCs" (which provide "pro-Tfh" signals) and Tregs (which consume IL-2) allow Tfh cell differentiation. To test this hypothesis, in Aim 1 we will first identify the specific DC subsets and activation state of DC that is required to prime Tfh cell responses, and the molecular mechanisms by which DC/Tregs/IL-2 interplay regulates this process. In Aim 2 we will determine the chemokine-chemokine receptor interactions that orchestrate "pro-Tfh DC" and Tregs encounters outside the T cell zone. In Aim 3 we will determine how IL-2 and other factors control the development of TFRs (which inhibit Tfh cell responses), so we can prevent TFR differentiation after vaccination. We believe that our work will significantly contribute to our understanding of how Tfh cell responses are initiated and reveal new strategies to elicit long-lived Ab responses to infection and vaccination. This proposal is innovative because it focuses on previously ignored, yet profoundly important, aspects of Tfh cell biology.