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.

PUBLIC HEALTH RELEVANCE: The influenza vaccine does not protect the elderly well against influenza, and we found that an important T cell necessary for the vaccine response has a reduced ability to provide this help in elderly, compared to young adults. We will investigate whether this effect is due to the T cells themselves or from a related regulatory cell, and whether the immune response to vaccination produces the same spectrum of T cells in different age groups. These data will help us understand the effects of aging on an important population of T cells for vaccine responses will help us design future vaccines for people whose immune systems have been weakened.