Connecting inflammation and senescence in the T follicular helper response to vac

描述(申请人提供)：在过去的60年里，流感疫苗接种一直用于临床预防流感感染。然而，有效接种疫苗的一个重大障碍是疫苗无应答的发生，这种情况在老龄化和慢性艾滋病毒感染等环境中发生得更频繁。不幸的是，这些人群通常也是感染致病和死亡风险最大的人群。流感疫苗接种后的主要免疫保护作用是中和B细胞产生的抗体，这需要T滤泡辅助细胞(TFH)CD4T细胞的帮助。根据表型、转录和功能分析，我们已经确定了一组循环中的TFH细胞(TFH样细胞)，它们与淋巴样TFH细胞高度相似。在基线时，与年轻人相比，老年人的TFH样细胞的循环频率减少，激活程度增加，功能能力减弱。接种疫苗后，TFH样反应与年轻人的抗体产生有关，但在老年人中减弱。相当多的证据表明，炎症和衰老之间有很强的关系，在感染艾滋病毒的情况下，可能会导致加速衰老。我们假设，在衰老和HIV感染的背景下，TFH样细胞上的慢性过度炎症的影响预测了衰老和对疫苗接种的抗体反应不良。本项目要解决的具体目标包括： 目的1：慢性炎症与TFH样细胞的衰老有关吗？我们已经证实了TFH样细胞的免疫激活和衰老，但尚不清楚全身炎症是否起到了作用。我将测试血清炎症标志物是否可以预测年轻人和老年人TFH样细胞的一系列全面的衰老变化，然后是与流感疫苗反应的相关性。 目的2：TFH样细胞内信号通路是否存在与衰老相关的变化？先前的研究表明，细胞因子受体下游的信号通路存在与年龄相关的变化。使用CyTOF质量细胞仪，我将评估STAT1、STAT3和STAT5对与TFH样细胞相关的细胞因子的反应。这将解决TFH反应差是否可能是细胞内在因素造成的问题。目的3：不受控制的HIV病毒血症是否会导致Tfh样细胞的提前衰老？艾滋病毒感染被认为会加速衰老，这可能是由于炎症增加所致。使用之前生成的一组接种流感疫苗的受试者，我将测试活跃的HIV病毒血症和血清炎症标志物是否预测疫苗反应减弱，以及与HIV无核型和未感染HIV的受试者相比，TFH样细胞是否表现出过度衰老。 总之，这些数据将阐明炎症和TFH样细胞衰老之间的关系。最终，目标是为那些有炎症和衰老证据的人创造更好的疫苗的机会。

DESCRIPTION (provided by applicant): For the past 60 years, influenza vaccination has been clinically used to prevent influenza infection. However, a significant obstacle to effective vaccination is the occurrence of vaccine nonresponses, which occur more frequently in settings such as aging and chronic HIV infection. Unfortunately, these populations are typically also the ones most at risk for morbidity and mortality from infection. The primary immune correlate of protection after influenza vaccination is neutralizing antibody production by B cells, which require help from T follicular helper (Tfh) CD4 T cells. We have identified a population of circulating Tfh cells (Tfh-like) that are highly similar to lymphoid Tfh based on phenotypic, transcriptional, and functional assays. At baseline, the elderly had a reduced circulating frequency, greater activation, and diminished functional ability in Tfh-like cells as compared to young adults. After vaccination, the Tfh-like response correlated with antibody production in the young but was blunted in the elderly. Considerable evidence suggests a strong relationship between inflammation and senescence and may lead to accelerated senescence in the context of HIV infection. We hypothesize that the effects of chronic, excessive inflammation on Tfh-like cells predict senescence and poor antibody responses to vaccination in the setting of aging and HIV infection. The specific aims to be addressed in this project are: Aim 1: Is chronic inflammation linked to senescence of Tfh-like cells? We have identified immune activation and senescence in Tfh-like cells but it is unknown if systemic inflammation plays a role. I will test whether serum inflammatory markers predict a comprehensive set of senescence changes in Tfh- like cells from young and elderly adults, followed by correlation to the influenza vaccine response. Aim 2: Are there senescence-related changes in intracellular signaling pathways in Tfh-like cells? Prior studies suggest age-related alterations in signaling pathways downstream of cytokine receptors. Using CyTOF mass cytometry, I will evaluate the STAT1, STAT3, and STAT5 response to cytokines relevant to Tfh-like cells. This will address whether poor Tfh responses could be due to cell- intrinsic factors. Aim 3: Does uncontrolled HIV viremia lead to early senescence in Tfh-like cells? HIV infection is thought to cause accelerated senescence which may be due to increased inflammation. Using a previously generated cohort of influenza-vaccinated subjects, I will test whether active HIV viremia and serum markers of inflammation predict diminished vaccine responses and whether excess senescence is manifested in Tfh-like cells when compared to HIV-aviremic and HIV-uninfected subjects. Together, these data will elucidate the relationship between inflammation and senescence in Tfh-like cells. Ultimately, the goal is create opportunities for better vaccines in those with evidence of inflammation and senescence.