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 #
5P01AG021600-10
Application #
8733493
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Connecticut
Department
Type
DUNS #
City
Farmington
State
CT
Country
United States
Zip Code
06030
Brahmakshatriya, Vinayak; Kuang, Yi; Devarajan, Priyadharshini et al. (2017) IL-6 Production by TLR-Activated APC Broadly Enhances Aged Cognate CD4 Helper and B Cell Antibody Responses In Vivo. J Immunol 198:2819-2833
Merani, Shahzma; Pawelec, Graham; Kuchel, George A et al. (2017) Impact of Aging and Cytomegalovirus on Immunological Response to Influenza Vaccination and Infection. Front Immunol 8:784
Swain, Susan L; Kugler-Umana, Olivia; Kuang, Yi et al. (2017) The properties of the unique age-associated B cell subset reveal a shift in strategy of immune response with age. Cell Immunol 321:52-60
Tabtabai, Ryan; Haynes, Laura; Kuchel, George A et al. (2017) Age-Related Increase in Blood Levels of Otolin-1 in Humans. Otol Neurotol 38:865-869
Masters, A R; Haynes, L; Su, D-M et al. (2017) Immune senescence: significance of the stromal microenvironment. Clin Exp Immunol 187:6-15
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
McElhaney, Janet E; Kuchel, George A; Zhou, Xin et al. (2016) T-Cell Immunity to Influenza in Older Adults: A Pathophysiological Framework for Development of More Effective Vaccines. Front Immunol 7:41
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
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; Lorenzo, Erica C; Masters, April R et al. (2016) Vaccine efficacy and T helper cell differentiation change with aging. Oncotarget 7:33581-94

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