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)
Type
Research Program Projects (P01)
Project #
5P01AG021600-10
Application #
8733490
Study Section
Special Emphasis Panel (ZAG1)
Program Officer
Fuldner, Rebecca A
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Connecticut
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Farmington
State
CT
Country
United States
Zip Code
06030
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
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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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