Infectious diseases, such as influenza, lead to high morbidity and mortality in elderly populations. In addition, the efficacy of vaccines is also significantly reduced for elderly populations, leaving them much more vulnerable to infection. While it is well known that the adaptive immune response to influenza infection and immunization declines with aging, the impact of specific age-related changes in T cell function remains to be elucidated. Defining the underlying defects in the immune response with aging in human populations is extremely difficult. Fortunately, mouse models allow us to precisely examine age-related changes in the immune system and determine the effect of these changes on a response to a particular pathogen. Thus, the key focus of this program is to assess the development of age-related changes in T cell function, define the mechanisms responsible for these defects and determine if they are also involved in declines in the human immune system. Project 1 "Impact of aging on CD4 immunity to flu" will examine the impact of age on CD4 T cell primary and memory responses and if this can be enhanced. Project 2 " Influence of aging on T follicular helper (Tfh) cells" will focus on examining the role of age-related changes in CD4 T cel cognate helper function for humoral responses and how this impacts the production of protective antibodies following vaccination. Project 3 "Impact of age on CD8+ T cell immunity to respiratory infection " will examine CDS T cell memory generation and function, which is dramatically reduced with aging possibly due to changes in homeostasis of memory T cell subsets. Project 4 "Impact of aging on the T cell repertoire and cellular immunity to influenza virus" will examine age- related changes in CD4 and CDS T cell repertoire and how these influence the ability to respond to influenza infection. The knowledge generated will allow the future development of strategies to overcome these defects and enhance vaccine efficacy for the elderly. Project 5 "Impact of aging on T cell responses to influenza vaccination" will translat findings in mouse models to studies in human naive and memory T cells from different age groups of vaccinated adults.

Public Health Relevance

While it is known that the adaptive immune response to influenza declines with aging, the impact of specific age-related changes in T cells and the role that they play in reduced immune responses remain to be elucidated. Thus, the key focus of this program is to assess the development of age-related changes in T cell function and repertoire and how these contribute to reduced immunity in animal and human models. This will allow the future development of strategies to overcome these defects and enhance vaccine efficacy for the elderly. REVIEW OF INDIVIDUAL COMPONENTS OF THE PROGRAM PROJECT CORE A: ADMINISTRATION;Dr. Laura Haynes, Core Leader (CL) DESCRIPTION (provided by applicant) The Administrative Core will provide administrative support and services to the Program Director and each Investigator in the program. The Program Director is responsible for supervising the Program and coordinating interactions between the Investigators, and will need the assistance of this Core to carry out this function. Oversight and coordination of this Program will be achieved by several mechanisms including monthly program meetings, meetings with the program's advisory committee and in house presentations of our progress. The Core will also provide statistical support, arrange travel, coordinate arrangements for invited seminar speakers, arrange internal seminars and meetings, prepare Progress Reports and coordinate presentations among the Investigators and in outside forums. The function of coordinating meetings and data exchange is particularly crucial to achieving the goals of the program to develop a comprehensive understanding of the impact of aging on the immune response to infectious disease and our ultimate attempts to find strategies to overcome those defects.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
7P01AG021600-09
Application #
8485477
Study Section
Special Emphasis Panel (ZAG1-ZIJ-1 (02))
Program Officer
Fuldner, Rebecca A
Project Start
2002-12-02
Project End
2017-05-31
Budget Start
2013-09-15
Budget End
2014-05-31
Support Year
9
Fiscal Year
2013
Total Cost
$1,867,162
Indirect Cost
$357,408
Name
University of Connecticut
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030
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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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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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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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