The proposed research addresses a series of questions that emerge from the fact that elderly persons have been exposed to a myriad of pathogens over their lifespan. This immunological history leads, in some cases, to the generation of expanded populations of memory CD8 T cells that have reached the stage of replicative senescence. In cell culture, CD8 T cells that reach this state after repeated rounds of antigen-driven proliferation show irreversible cell cycle arrest, permanent loss of CD28 gene expression, apoptosis resistance, poor response to stress, altered cytokine profiles, and shortened telomeres compared to their CD28+ progenitors. Clinical studies have identified correlations between CD8 T cells showing characteristics of replicative senescence and such diverse health outcomes as reduced responsiveness to influenza vaccination and osteoporotic fractures. The central hypothesis of the proposed research is that the high proportion of senescent CD8 T cells present in vivo exerts deleterious effects on both immune and non-immune organ systems during aging. To further elucidate the underlying mechanisms by which CD8 T cell replicative senescence may mediate pleiotropic physiological effects, the following specific aims will be addressed: (1) To determine the role of senescent CD8 T cells on immune function. Direct cell interaction and cell-free supernatants from senescent cultures will be evaluated for their impact on CD4 T cell help, CD8 effector functions, antigen-presentation and antibody production. (2) To evaluate genetic and non-genetic manipulations to reverse CD8 T cell replicative senescence. Lentivirus vectors containing CD28 or telomerase, reduced levels of oxygen, and exposure to estrogen (which affects several genes associated with senescence) will be compared for effects on telomere/telomerase dynamics, population doublings, CD8 T cell immune functions, and immune modulatory functions identified in Aim 1. (3) To investigate the role of senescent CD8 T cells in osteoporosis, based on the well-documented effects of chronic immune activation on bone integrity and on the identification of cytokine-producing T cells within the bone marrow. Early passage and senescent CD8 T cells will be compared for effects on the maturation, differentiation, and function of osteoclasts (the bone resorbing cells) and osteoblasts (the bone forming cells). In vitro observations will be confirmed using a murine model of osteoporosis. In sum, the proposed studies will provide an unparalleled opportunity to experimentally dissect the genetic and molecular basis of several fundamental aspects of human immunological aging that significantly impact health and longevity.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG023720-03
Application #
7189082
Study Section
Special Emphasis Panel (ZRG1-ASG (01))
Program Officer
Fuldner, Rebecca A
Project Start
2005-02-15
Project End
2010-01-31
Budget Start
2007-04-01
Budget End
2008-01-31
Support Year
3
Fiscal Year
2007
Total Cost
$290,478
Indirect Cost
Name
University of California Los Angeles
Department
Pathology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Dock, Jeffrey N; Effros, Rita B (2011) Role of CD8 T Cell Replicative Senescence in Human Aging and in HIV-mediated Immunosenescence. Aging Dis 2:382-397
Effros, Rita B (2011) Telomere/telomerase dynamics within the human immune system: effect of chronic infection and stress. Exp Gerontol 46:135-40
Parish, Stanley T; Wu, Jennifer E; Effros, Rita B (2010) Sustained CD28 expression delays multiple features of replicative senescence in human CD8 T lymphocytes. J Clin Immunol 30:798-805
Graham, Lucia S; Tintut, Yin; Parhami, Farhad et al. (2010) Bone density and hyperlipidemia: the T-lymphocyte connection. J Bone Miner Res 25:2460-9
Tseng, Wendy; Graham, Lucia S; Geng, Yifan et al. (2010) PKA-induced receptor activator of NF-kappaB ligand (RANKL) expression in vascular cells mediates osteoclastogenesis but not matrix calcification. J Biol Chem 285:29925-31
Parish, Stanley T; Kim, Sarah; Sekhon, Rekha K et al. (2010) Adenosine deaminase modulation of telomerase activity and replicative senescence in human CD8 T lymphocytes. J Immunol 184:2847-54
Parish, Stanley T; Wu, Jennifer E; Effros, Rita B (2009) Modulation of T lymphocyte replicative senescence via TNF-{alpha} inhibition: role of caspase-3. J Immunol 182:4237-43
Chen, Wilbur H; Kozlovsky, Bernard F; Effros, Rita B et al. (2009) Vaccination in the elderly: an immunological perspective. Trends Immunol 30:351-9
Graham, Lucia S; Parhami, Farhad; Tintut, Yin et al. (2009) Oxidized lipids enhance RANKL production by T lymphocytes: implications for lipid-induced bone loss. Clin Immunol 133:265-75
Effros, Rita B (2009) Kleemeier Award Lecture 2008--the canary in the coal mine: telomeres and human healthspan. J Gerontol A Biol Sci Med Sci 64:511-5

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