Influence of aging on T follicular helper (Tfh) cells

增龄对T滤泡辅助性T细胞的影响免疫系统对疫苗的反应能力，如流感疫苗，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CD4T细胞启动和Tfh分化的变化是否会导致接种疫苗后体液反应的减少。为了实现这一点，我们开发了模型系统，允许我们探索该领域仍未得到解答的具体问题。只有当这些问题得到解决和解答后，我们才能开始设计克服这些问题和提高老年人口疫苗效力的战略。在我们的研究中，我们使用了采用转移模型，使我们能够单独检查衰老对免疫反应的特定组成部分的影响。在确定年龄对TFH细胞功能的影响以及这如何影响接种疫苗的体液反应方面，我们已经取得了很大进展。TFH最近被定义为为B细胞反应提供同源帮助的CD4T细胞。它们表达特定的细胞表面标记，产生特定的细胞因子，并可在疫苗接种后的生发中心(GC)内找到。我们的研究揭示了与TFH和随着年龄增长的体液免疫反应有关的三个要点：(1)TFH功能存在固有的年龄相关缺陷，导致B细胞扩增、分化、免疫球蛋白生成和亲和力成熟减少；(2)除了TFH的内在年龄相关变化外，我们还确定次级淋巴器官的微环境也存在与年龄相关的变化，包括CCL21表达的变化，这与CD 4 T细胞的启动减少有关；(3)与青年小鼠相比，完整老年小鼠接种疫苗后产生的抗体(Ab)显示出保护能力显著降低和谱系发生变化。总而言之，我们认为这些因素导致Tfh分化减少，老年人对疫苗接种产生强烈反应的能力降低，最终导致对后续感染的保护减少。在这项建议中，我们将研究导致衰老的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反应的产生。我们的假设是，由于T细胞内在和外在的变化，与年龄相关的TFH激发的减少是疫苗免疫体液反应降低的主要因素，加强这种激发可以改善老年人的免疫反应。

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.