instmctions): The capacity of the immune system to mediate responses to new infections declines with age. This decline poses substantial problems from a clinical standpoint since the efficacy of vaccines administered to the elderly is severely compromised. For example, influenza vaccines mediate only limited protection in the elderly, a population that is particularly vulnerable to respiratory virus infections, such as influenza. Many of the immune defects that accumulate with age have been mapped to CD4* T cells. CD4* T cells from aged individuals are more difficult to prime, proliferate poorly to antigen challenge, are less efficient at generating T cell memory, and are less effective at helping antibody responses to new infections or vaccines. In contrast, much less is known about the impact of age on the memory CDS* T cell pool. We and others have shown that memory CDS* T cells generated in aged mice has a reduced capacity to mediate recall responses. In addition, we have shown that memory CDS* T cell pools progressively degrade with increasing age. This includes the development of antigen-specific T cell clonal expansions (TCE) that lack the capacity to mediate recall responses and other changes in the composition and quality of memory CDS* T cell pools. The mechanisms underlying the poor quality of CDS* T cell memory in aged mice and the factors that control the age-related degradation of CDS* T cell memory are not understood. We hypothesize that the loss of cellular recall responses to respiratory virus infections in aged animals reflects the presence of distinct subpopulations of memory CDS* T cells that differ in their longevity and responsiveness. To address this hypothesis, we will determine how and when the memory T cell pool degrades with increasing age and the mechanisms that control the development of different memory T cell subsets.
The specific Aims are to (i) identify the mechanisms that control the development of defective memory generation in aged mice and (ii) determine when and how dysregulation of the memory T cell pool impacts recall responses to respiratory virus infections. These studies will integrate with other Projects in the Program that address the impact of aging on the quality of cellular and humoral memory generated in aged mice.

Public Health Relevance

Respiratory virus infections, such as those mediated by influenza, constitute a major human health problem in the United States. Thus, there is an urgent need to understand immunity to these viruses, especially in the elderly. The goal of the current studies is to better understand immunity in the aged with a view to the development of more effective vaccines for this population.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
2P01AG021600-08A1
Application #
8261475
Study Section
Special Emphasis Panel (ZAG1-ZIJ-1 (02))
Project Start
Project End
2013-05-31
Budget Start
2012-06-15
Budget End
2013-05-31
Support Year
8
Fiscal Year
2012
Total Cost
$387,823
Indirect Cost
$188,686
Name
Trudeau Institute, Inc.
Department
Type
DUNS #
020658969
City
Saranac Lake
State
NY
Country
United States
Zip Code
12983
Lefebvre, Julie S; Lorenzo, Erica C; Masters, April R et al. (2016) Vaccine efficacy and T helper cell differentiation change with aging. Oncotarget 7:33581-94
Bartley, Jenna M; Pan, Sarah J; Keilich, Spencer R et al. (2016) Aging augments the impact of influenza respiratory tract infection on mobility impairments, muscle-localized inflammation, and muscle atrophy. Aging (Albany NY) 8:620-35
Lefebvre, Julie S; Masters, April R; Hopkins, Jacob W et al. (2016) Age-related impairment of humoral response to influenza is associated with changes in antigen specific T follicular helper cell responses. Sci Rep 6:25051
Zhou, Xin; Hopkins, Jacob W; Wang, Chongkai et al. (2016) IL-2 and IL-6 cooperate to enhance the generation of influenza-specific CD8 T cells responding to live influenza virus in aged mice and humans. Oncotarget 7:39171-39183
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Yang, Rui; Lirussi, Dario; Thornton, Tina M et al. (2015) Mitochondrial Ca²⁺ and membrane potential, an alternative pathway for Interleukin 6 to regulate CD4 cell effector function. Elife 4:
Lanzer, Kathleen G; Johnson, Lawrence L; Woodland, David L et al. (2014) Impact of ageing on the response and repertoire of influenza virus-specific CD4 T cells. Immun Ageing 11:9
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
Swain, Susan L; Blomberg, Bonnie B (2013) Immune senescence: new insights into defects but continued mystery of root causes. Curr Opin Immunol 25:495-7

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