Effects of aging on the T follicular helper response to influenza vaccine

衰老对 T 滤泡辅助细胞对流感疫苗反应的影响

• 批准号: 9205486
• 负责人: Ramin Herati
• 金额: $ 19.43万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9205486
• 关键词: Activities of Daily Living; Address; Adjuvant; Adult; Affect; Age; Aging; Antibodies; Antibody Formation; Antibody Response; B-Lymphocytes; Biostatistical Methods; CD4 Positive T Lymphocytes; Cell Survival; Cells; Cessation of life; Clinical; Clone Cells; Complex; Computing Methodologies; Cytokine Receptors; Data; Dose; Elderly; Etiology; Evaluation; Frequencies; Functional disorder; Future; Goals; Helper-Inducer T-Lymphocyte; Human; Immune response; Immune system; Immunoglobulin Class Switching; Immunology; In Vitro; Individual; Inferior; Inflammatory; Influenza; Influenza vaccination; Interleukin-10; Interleukin-2; Interleukin-6; Knowledge; Measures; Mentors; Mentorship; Morbidity - disease rate; Mus; Pathway interactions; Pharmacology; Population; Predisposition; Production; Receptor Cell; Regimen; Regulation; Research Personnel; Resolution; Signal Pathway; Signal Transduction; Structure of germinal center of lymph node; T cell response; T-Cell Receptor; T-Lymphocyte; Techniques; Testing; Vaccination; Vaccine Design; Vaccines; age effect; age group; age related; anti-influenza; base; career; cytokine; design; high risk; improved; influenza virus vaccine; inhibitor/antagonist; interleukin-21 receptor; mortality; neutralizing antibody; next generation sequencing; predicting response; prevent; public health relevance; receptor; response; seasonal influenza; vaccination strategy; vaccine efficacy; vaccine response; young adult

DESCRIPTION (provided by applicant): For the past 60 years, influenza vaccination has been used to prevent influenza infection. However, some individuals do not respond to vaccination, which occurs more frequently with age. Unfortunately, this population is at highest risk for morbidity and mortality from influenza. Protection from influenza is derived from neutralizing antibody production by B cells, which require help from T follicular helper (Tfh) CD4 T cells. We have identified circulating Tfh (cTfh) that have reduced B cell help ability in the elderly and did not respond as well to influenza vaccination compared to young. We hypothesize that abnormal cTfh function and responses to vaccination predict age-related reduction in influenza-specific antibody responses to vaccination. These studies will clarify the etiology behind reduced cTfh functional ability in the elderly. These studies will inform future rational vaccine design efforts and improve our ability to predict vaccine nonresponses. The specific aims to be addressed are: * Aim 1: Do cell-intrinsic changes in signaling pathways explain cTfh dysfunction with aging? We have identified reduced responsiveness to cytokines in cTfh from the elderly compared to young. We hypothesize that other signaling pathways may be compromised. We will assess the effect of aging on STAT signaling, the ability of cTfh from the elderly to effectively maintain direct contact with B cells, and whether pharmacological agents can improve cTfh function. * Aim 2: Do T follicular regulatory cells have an age-related effect on the vaccine response? We have identified T follicular regulatory cells (cTfr) which suppress B cell help ability of cTfh. We will interrogate the suppressive effects of cTfr and assess whether there is a cTfr response to vaccination that helps improve prediction of antibody responses. * Aim 3: Do the elderly generate a less diverse Tfh repertoire after vaccination? Many studies have identified narrowed repertoire in T cells with aging. Here, we will investigate the repertoire in cTfh based on the T cell receptor to establish whether there is a difference in breadth of repertoire in the young and elderly, identify public clonotypes common between individuals, and assess lineage relationships. Combined with knowledge of the antibody response to vaccination, these data will identify if narrowed Tfh repertoire can correlate with antibody responses to vaccination. With Dr. Wherry as my primary mentor at UPenn and strong institutional support, I have been investigating T cell responses to vaccination, with focus on the Tfh subset, in the setting of aging. I have assembled a mentorship committee, outlined a didactic plan in biostatistics and computational methods, and identified milestones that will serve as the basis for my career as an independent investigator studying T cell responses in human immunology.

描述（由申请人提供）：在过去的60年里，流感疫苗一直被用来预防流感感染。然而，有些人对疫苗接种没有反应，这种情况随着年龄的增长而更常见。不幸的是，这一人群患流感的发病率和死亡率最高。对流感的保护来自于B细胞产生的中和抗体，这需要T滤泡辅助（Tfh） CD4 T细胞的帮助。我们已经确定循环Tfh （cTfh）降低了老年人的B细胞帮助能力