Influence of aging on T follicular helper (Tfh) cells

衰老对T滤泡辅助细胞（Tfh）的影响。免疫系统对接种疫苗（如流感疫苗）的反应能力随着年龄的增长而下降。为了开始了解这种下降的机制，重要的是要确定年龄相关的CD 4 T细胞引发和Tfh分化的变化是否会导致疫苗接种后体液应答的减少。为了实现这一目标，我们开发了模型系统，使我们能够探索在这一领域仍然没有答案的具体问题。只有当这些问题得到解决和回答，我们才能开始设计克服这些问题和提高老年人疫苗效力的战略。在我们的研究中，我们使用过继转移模型，使我们能够单独检查衰老对免疫反应特定组分的影响。我们在确定年龄对Tfh细胞功能的影响以及这如何影响疫苗接种的体液反应方面取得了很大进展。Tfh最近被定义为B细胞应答提供同源帮助的CD 4 T细胞。它们表达特定的细胞表面标志物，产生特定的细胞因子，并且可以在接种疫苗后的生发中心（GC）内发现。我们的研究揭示了Tfh和体液免疫应答随衰老的三个重要方面：（1）Tfh功能存在与年龄相关的内在缺陷，导致B细胞增殖、分化、IgG产生和亲和力成熟减少;（2）除了Tfh的内在年龄相关变化外，我们已经确定次级淋巴器官的微环境也存在年龄相关变化，包括CCL 21表达的变化，这有助于减少CD 4 T细胞引发;（3）当与年轻小鼠相比时，接种完整的老年小鼠后产生的抗体（Ab）表现出显著降低的保护能力和改变的库。总之，我们认为这些因素有助于减少Tfh分化和降低老年人对疫苗接种产生强烈反应的能力，最终导致对后续感染的保护减少。在这项提案中，我们将研究负责老年Tfh功能降低/改变的机制，以及佐剂如何克服这些缺陷。重要的是，我们还将研究这如何影响流感疫苗接种后保护性体液应答的产生。我们的假设是，Tfh引发的年龄相关的减少，这是由于T细胞的内在和外在的变化，是一个主要因素，减少体液免疫接种反应，增强这种引发可以提高老年人的免疫应答。

Influence of aging on T follicular helper (Tfh) cells. The ability of the immune system to respond to vaccinations, such as that for influenza, declines with age. To begin to understand the mechanisms responsible for this decline, it is important to determine if age-related changes in CD4 T cell priming and Tfh differentiation lead to reductions in humoral responses following vaccination. To accomplish this, we have developed model systems that permit us to explore specific questions that remain unanswered in this field. Only when these questions are addressed and answered can we then begin to design strategies for overcoming them and enhancing vaccine efficacy for elderly populations. In our studies, we have used adoptive transfer models that allow us to examine the influence of aging on specific components of the immune response individually. We have made a great deal of progress in determining the influence of age on the function of Tfh cells and how this impacts the humoral response to vaccination. Tfh have been recently defined as CD4 T cells that provide cognate help for B cell responses. They express specific cell surface markers, produce specific cytokines and can be found within germinal centers (GC) following vaccination. Our studies have revealed three important points regarding Tfh and humoral immune responses with aging: (1) There are intrinsic age-related defects in Tfh function that lead to reduced B cell expansion, differentiation, IgG production and affinity maturation; (2) In addition to intrinsic age-related changes in Tfh, we have determined that there are age-related changes in the microenvironment of secondary lymphoid organs, including changes in CCL21 expression, which contributes to reduced CD4 T cell priming; (3) Antibodies (Ab) generated following vaccination of intact aged mice exhibit significantly reduced protective capacity and an altered repertoire when compared to young mice. Together, we propose that these factors contribute to reduced Tfh differentiation and the reduced ability to generate a robust response to vaccination in aged individuals, ultimately resulting in reduced protection from subsequent infection. In this proposal, we will examine the mechanisms responsible for the reduced/altered function of aged Tfh and how adjuvants can overcome these defects. Importantly, we will also examine how this impacts the generation of a protective humoral response following infiuenza vaccination. Our hypothesis is that age-related reductions in Tfh priming, which are due to both T cell intrinsic and extrinsic changes, are a major factor in the reduced humoral response to vaccinations and that enhancing this priming can improve the immune response in aged individuals.