B cell and T cell Determinants of Influenza Vaccine Responses in the Elderly
2011 new Scholar Award in aging
Understanding of the biology of aging humans and finding ways of prolonging good health in the elderly are important goals for modern health care and research. The immune system appears to become less effective with age, rendering the elderly more prone to severe infections, either from routine viruses and bacteria encountered in the environment, or via reactivation of latent viruses such as the chicken pox virus that causes ‘shingles’ when it can no longer be effectively controlled in an elderly person.
There is also an apparent decrease in the response to vaccination in the elderly, but the reasons for this are unclear, partly because the features that make vaccines effective in people of any age are not fully mapped out. Some of the functional problems of vaccine responses in the elderly likely result from decreased effectiveness of T cells of the immune system, which are no longer generated in the same numbers that they were earlier in life, and which appear to become less diverse and more limited in their ability to recognize diverse pathogens in elderly people. In addition, a virus that chronically infects many people, cytomegalovirus, appears to stimulate significant portions of the total T cell populations in the body to respond to it, potentially affecting responses to other pathogens or protective responses that would otherwise be stimulated by vaccines. In addition to T cell defects, age-related changes in the B cells that make protective antibodies may also contribute to the decreased vaccine responses, but many features of how these cell populations change with aging are still unknown.
Despite this initial understanding of age effects on B cells and T cells, we currently have little ability to predict whether an individual elderly person will be protected effectively by vaccination, and no generally accepted assay for vaccine effectiveness at early time points. A more detailed mapping of the size and diversity of B cell and T cell responses in effective vaccination, and failed vaccination, would expand basic scientific knowledge of aging changes in the immune system, and could offer better methods for monitoring patient care in future.
We will be studying a relatively large group of elderly subjects (60 people) and younger subjects (30 people) from blood samples taken before and after influenza vaccination over a series of 3 years. We make use of new high-throughput DNA sequencing methods to perform intensive analysis of the parts of the genome of B cells and T cells that encode the surface receptors for foreign antigens, and we can use this approach to track the cells that respond to a vaccination event, to see how much they are stimulated to divide, and how many different groups of B cells and T cells respond to the vaccine. In addition, the parts of the genome we are sequencing act as a ‘fingerprint’ of the individual B cell or T cell, so we can use this information to track the responding cells from one year to the next, to see if the same populations of cells respond to different strains of influenza vaccine. Using this experimental approach, paired with other measurements of immune system function, such as measurement of cell surface proteins, gene expression levels and the secretion of small proteins that signal to other cells in the immune system, we should be able to clarify some of the basic features of these aspects of human immune system aging, which could form the basis for new clinical tests for vaccination efficacy, and potentially guide re-vaccination of some individuals, or help in the development of more effective vaccines.