Regulation of T-cell dependent B cell responses to influenza

 描述（由申请方提供）：产生长寿命、高亲和力抗体（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，了解控制产生持久保护性Ab反应的机制至关重要。滤泡辅助性T细胞（Tfh）是一种独特的CD 4 + T细胞亚群，其表达高水平的CXCR 5并定位于B细胞滤泡中，在促进长寿命Ab应答中发挥重要作用。事实上，在缺乏Tfh细胞的情况下，长期抗体应答受损，对病原体的保护受到损害。因此，我们必须了解如何操纵Tfh应答，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细胞反应如何启动的理解非常有限。最近的研究表明，Tfh细胞最初是由 通过树突状细胞（DC），这表明我们可能能够开发优先激活DC以促进Tfh细胞引发的佐剂，或将疫苗抗原靶向那些优先诱导Tfh细胞的DC。不幸的是，我们不知道是什么信号引导DCs促进Tfh细胞分化或DCs的哪些特定亚群引发Tfh细胞应答。因此，该提案的长期目标是确定病毒特异性Tfh细胞如何被DC引发，这将有助于我们确定可用于增强Tfh细胞应答的佐剂的性质。重要的是，尽管一些研究表明TfH，特别是T滤泡调节（TFR）细胞，抑制TfH和GC B细胞应答，但我们最近发现TfH促进TfH和B细胞对流感的应答。从机制上讲，Tregs通过限制IL-2（Tfh的有效抑制剂）的生理可用性来促进流感特异性Tfh细胞的发育 细胞分化因此，除了DC之外，Tfh也是正常Tfh细胞应答所需的。在这个提议中将要检验的中心假设是，Tfh细胞被启动， 在T细胞区域外的特定低IL-2微环境中，其中“pro-Tfh DC”（其提供“pro-Tfh”信号）和Tfh（其消耗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细胞应答所需的特定DC亚群和DC的活化状态，以及DC/Tfh/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-趋化因子受体相互作用，其协调“前Tfh DC”和T细胞区外的Tfh相遇。在目标3中，我们将确定IL-2和其他因素如何控制TFR的发展（抑制Tfh细胞反应），因此我们可以防止接种后TFR分化。我们相信，我们的工作将大大有助于我们了解Tfh细胞反应是如何启动的，并揭示了新的策略，以引发对感染和疫苗接种的长期抗体反应。该提案具有创新性，因为它关注的是Tfh细胞生物学中以前被忽视但极其重要的方面。

 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.