Immune function declines with age, resulting in increased susceptibility of aged individuals to infection and impaired responses to vaccines. The ability to generate T cell responses to newly encountered antigens and to respond to vaccination is dependent on the maintenance of a diverse repertoire of T cells. Aging is associated with reduced repertoire diversity in both mouse and human. We have previously shown that there is an age-associated reduction in repertoire diversity among naive CDS T cells, and using the mouse influenza virus model have defined profound consequences of reduced repertoire for primary and protective immunity of aged mice to influenza virus. We have new preliminary data showing that repertoire perturbations also impact CD4 T cell responses to influenza virus epitopes. Because of reduction of the naive repertoire in aged individuals, we hypothesize that aging results in a greater contribution of fortuitously cross-reactive memory cells to the response to new infections, and that this will lead to stochastic responses in individuals, often of lower avidity. In support of this, we have preliminary data showing that fortuitously cross-reactive memory cells from influenza-naive aged mice can respond to influenza virus epitopes, and in Aim 1 we will determine the contribution of cross reactive memory to the response to new infections, and the implications for cellular immunity.
In Aim 2 we will focus on experimental interventions to enhance diversity of the T cell repertoire and protective immunity in aged mice. In the context of other projects in the Program, these studies will address mechanisms underiying the age-associated decline in cellular immunity which is essential for the goal of designing better therapies and vaccines for the elderiy.

Public Health Relevance

Relevance: Our ability to respond to infection or vaccination decreases dramatically as we age. Elderiy individuals are significantly more susceptible to infections than the young, and respiratory infections, such as those caused by influenza virus, are a major cause of death and hospitalization in this group. Vaccines are therefore essential but, unfortunately, the elderiy are also more difficult to vaccinate. The studies proposed will determine the mechanisms underiying decreased immunity of the elderly, and will begin to test ways of overcoming these deficiencies in order to design better vaccines.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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Special Emphasis Panel (ZAG1-ZIJ-1 (02))
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Trudeau Institute, Inc.
Saranac Lake
United States
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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

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