Clinical studies have shown that older persons are more susceptible to multiple diseases including cancer, autoimmunity and infections and manifest an impaired response to vaccinations. This implies that the elderly have aberrant immune responses. Although several earlier studies have shown that aging impairs T cell function, most of these studies were performed prior to the appreciation of the innate arm of the immune system. The Toll like receptors (TLRs) are critical innate immune receptors on dendritic cells (DCs), which represent the most powerful antigen presenting cells that respond to specific microbial motifs. Upon TLR ligation DCs are essential for effective priming of both na'i've CD4+ and CD8+ T cells. However, the impact of aging on DC-dependent immune function is unclear. It is critical to answer this fundamental question if we are to develop effective therapies to improve immune function in older people. The urgency of this issue is rising since the elderly subpopulation in western countries is rapidly increasing and posing a heavy burden on our health care resources. Our preliminary data using experimental allogeneic murine models provide novel evidence that TLR immunity in myeloid DCs remains preserved with aging in response to a broad range of TLR agonists. Therefore, in this proposal, we are in a strong position to test the hypothesis that aging specifically impairs adaptive intrinsic CD8+ T cell immune responses to viral infection with preserved innate DC-dependent TLR immune priming. Specifically, we will employ a murine LCMV infection model to discern if aging impairs either innate DC-dependent TLR immune priming or adaptive intrinsic CD8+ anti-viral immunity (aims 1 and 2).
In aim 3 we will test the hypothesis that specific TLR agonists augment the proinflammatory cytokine milieu and boost primary anti-viral CD8+ T immunity in the aged host. In selected cases we will use alternate pathogens to examine if our findings are applicable to other viral infections. Therefore, this proposal will provide critical, fundamental information as to whether aging impairs innate DC- dependent TLR immunity or adaptive intrinsic CD8+ T cell immune responses during viral infection and will provide insights as to whether TLR agonists can act as adjuvants and restore primary immunity in the aged host. The resulting information will be essential to accelerate clinically relevant therapeutic protocols that will augment the immune response and help restore health in older people.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG028082-05
Application #
8101203
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Fuldner, Rebecca A
Project Start
2007-07-15
Project End
2012-08-31
Budget Start
2011-07-01
Budget End
2012-08-31
Support Year
5
Fiscal Year
2011
Total Cost
$317,467
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Elpek, Kutlu G; Cremasco, Viviana; Shen, Hua et al. (2014) The tumor microenvironment shapes lineage, transcriptional, and functional diversity of infiltrating myeloid cells. Cancer Immunol Res 2:655-67
Wong, Christine; Goldstein, Daniel R (2013) Impact of aging on antigen presentation cell function of dendritic cells. Curr Opin Immunol 25:535-41

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