Impact of Aging on CD4 Immunity to Flu. We have defined extensive age-associated defects in immune system response particulariy in naive CD4 T cells that give poor effector responses and the generation of impaired memory cells. In the first funding cycle we found that pro-inflammatory cytokines (IL-1, IL-6 and TNFa) could reverse many of the defects in effector generation, and that surrogates of viral products that stimulate immune cells, called TLR agonists, induce production of these by DC presenting antigen to the T cells. We identified IL-6 production by DC during the cognate interaction as key for increasing expansion and blocking death of responding aged naive CD4 T cells. The activation also restores memory responses to some extent. Now we will define the molecular pathways leading to the "rescue" of the naTve CD4 T responses using a combination of reductionist in vitro approaches and carefully designed adoptive transfer models, that will allow us to determine the cellular and molecular mechanisms involved. We will use highly tractable TcR Tg models as well as polyclonal studies to dissect mechanisms. We will analyze rescue pathways in vivo as well as extend the studies to CDS T cells in mouse and to human CD4 and CDS T cells (part of Project 5). These studies will generate important information that could contribute to the development in future of better strategies, using TLR agonists, to more effectively vaccinate the elderiy and we expect to be able to develop a unified theory of how aging develops in T cells, what defects exist and which can be overcome and how in mice and man.

Public Health Relevance

In the elderly, influenza results in high morbidity and mortality and current subunit vaccines are largely ineffective. Pandemic strains completely evade previous Ab-based immunity induced by current vaccines. Because their immune systems are defective and they respond to poorly to new infections, the elderly are at great risk. Our studies will evaluate whether TLR agonists, can overcome immune defects and may be combined with vaccines to give robust T cell immunity that will be broadly reactive to new strains.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
2P01AG021600-08A1
Application #
8261469
Study Section
Special Emphasis Panel (ZAG1-ZIJ-1 (02))
Project Start
2011-12-01
Project End
2013-05-31
Budget Start
2012-06-15
Budget End
2013-05-31
Support Year
8
Fiscal Year
2012
Total Cost
$340,998
Indirect Cost
Name
Trudeau Institute, Inc.
Department
Type
DUNS #
020658969
City
Saranac Lake
State
NY
Country
United States
Zip Code
12983
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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
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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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