Declining immune function of older adults Is a hallmark of aging and affects the ability of this vulnerable population to resist influenza and respond to vaccination. Rising hospitalization and death rates due to influenza over the last two decades in spite of widespread influenza vaccination programs, call for more effective influenza vaccines in the older population. There have been major advances in vaccine technology but the phases of clinical development are entirely dependent on antibody responses as correlates of protection and measures of vaccine efficacy. This approach to vaccine development lacks a mechanistic understanding of the age-related changes In the development and maintenance of T cell memory in the response to influenza and Influenza vaccination. This project provides a translational approach to understanding how mechanisms of decline with aging of influenza-specific T cell memory responses found in mouse models, apply to studies of peripheral blood mononuclear cells (PBMC) from older people. How T cell memory may be generated or restimulated in response to adjuvanted influenza vaccine formulations is of particular interest. Our long-term goal is to understand how aging affects the Immune response to Influenza and how vaccines could be designed to provide better protection in older people. We will conduct studies to translate recent promising findings In mouse models to establish whether the insights gained will be applicable to comparable human naive and memory CD4 and CD8 T cells. This 5-year proposal will address the following aims: 1) Elucidate defects in the generation of effector and memory functions in aged naive CD4+ T cells and determine their potential reversibility. 2) Identify age-related changes in the phenotype and function of memory T-cell subsets responding to live influenza virus challenge. 3) Determine how CD4 and CD8 T cell responses to influenza vaccination may be enhanced by adjuvants/vaccines in older adults.

Public Health Relevance

Relevance: While it is well recognized that current split-virus vaccines provide limited protection in older people, strategies that completely rely on antibody titers have failed to develop more effective vaccines. A mechanistic approach to vaccine development and a greater understanding of how to improve aged memory T cell responses to influenza is needed;an adjuvanted vaccine formulation holds the greatest promise for better protection in this population.

National Institute of Health (NIH)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Connecticut
United States
Zip Code
Zhang, Wenliang; Brahmakshatriya, Vinayak; Swain, Susan L (2014) CD4 T cell defects in the aged: causes, consequences and strategies to circumvent. Exp Gerontol 54:67-70
McKinstry, K Kai; Dutton, Richard W; Swain, Susan L et al. (2013) Memory CD4 T cell-mediated immunity against influenza A virus: more than a little helpful. Arch Immunol Ther Exp (Warsz) 61:341-53
Lefebvre, Julie S; Haynes, Laura (2013) Vaccine strategies to enhance immune responses in the aged. Curr Opin Immunol 25:523-8
Haynes, Laura; Swain, Susan L (2012) Aged-related shifts in T cell homeostasis lead to intrinsic T cell defects. Semin Immunol :
Blackman, Marcia A; Woodland, David L (2011) The narrowing of the CD8 T cell repertoire in old age. Curr Opin Immunol 23:537-42
Jones, Stephen C; Brahmakshatriya, Vinayak; Huston, Gail et al. (2010) TLR-activated dendritic cells enhance the response of aged naive CD4 T cells via an IL-6-dependent mechanism. J Immunol 185:6783-94
Kohlmeier, Jacob E; Connor, Lisa M; Roberts, Alan D et al. (2010) Nonmalignant clonal expansions of memory CD8+ T cells that arise with age vary in their capacity to mount recall responses to infection. J Immunol 185:3456-62
Takamura, Shiki; Roberts, Alan D; Jelley-Gibbs, Dawn M et al. (2010) The route of priming influences the ability of respiratory virus-specific memory CD8+ T cells to be activated by residual antigen. J Exp Med 207:1153-60
Tsukamoto, Hirotake; Huston, Gail E; Dibble, John et al. (2010) Bim dictates naive CD4 T cell lifespan and the development of age-associated functional defects. J Immunol 185:4535-44
Maue, Alexander C; Eaton, Sheri M; Lanthier, Paula A et al. (2009) Proinflammatory adjuvants enhance the cognate helper activity of aged CD4 T cells. J Immunol 182:6129-35

Showing the most recent 10 out of 27 publications