Age-associated changes occur in T cell immunity, contributing to increased risk of infection and malignancy. Probably, the most intriguing alteration in CD8+ T cell immunity with aging is memory CD8+ T cell expansion although the mechanism(s) and the consequences of this phenomenon are largely unknown. Recently, my lab investigated whether the age-associated expansion of memory CD8+ T cells was secondary to increased expression of IL-7 receptor alpha chain (IL-7Ra) which is critical for CD8+ T cell survival. In this study, cells expressing IL-7Ra high and low were found in a subset of memory cells called CD45RA+ effector memory (EMCD45RA+, CD45RA+ CCR7-) CD8+ T cells. In contrast to the expectation, the elderly (age ?: 65) had expansion of IL-7Ra low EMCD45RA+ CD8+ T cells (25% of total CD8+ T cells) compared to the young (age ? 40). This finding raises several questions. How does such cell expansion occur? What is the immunologic consequence(s) of this cell expansion? The expansion of IL-7Ra low EMCD45RA+ CD8+ T cells could be secondary to chronic antigen stimulations by infections such as cytomegalovirus (CMV), which has been linked to the expansion of memory CD8+ T cells with aging. However, these cells poorly survive and proliferate in response to IL-7 and TCR triggering, respectively, indicating that neither IL-7 nor chronic TCR triggering alone is sufficient explanation for this phenomenon. Of interest, IL-7Ra low CD8+ T cells nicely proliferate and expand in response to IL-15 and a combination of IL-15 and TCR triggering, which suggests the role for IL-15 in expanding IL-7Ra low EMCD45RA+ CD8+ T cells. Thus, I hypothesize that IL-15 is critical for expanding IL-7Ra low EMCD45RA+ CD8+ T cells with aging via inducing antigen-independent (IL-15 alone) and -dependent (TCR triggering, possibly CMV, with IL-15) cell proliferation, and such expanded cells have altered functions. This hypothesis will be addressed with the following specific aims: 1) Investigate whether the expansion of IL-7Ra low EMCD45RA+ CD8+ T cells with aging is directly related to CMV infection; 2) Determine whether the expansion of IL-7Ra low EMCD45RA+ CD8+ T cells with aging steins from alterations in IL-15-mediated CD8+ T cell proliferation; and 3) Investigate whether expanded IL-7Ra low EMCD45RA+ CD8+ T cells in the elderly have altered function. The results of this study will advance our understanding about the effect of aging on the immune system, leading to better protection against infection and tumors. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG028069-02
Application #
7483094
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Fuldner, Rebecca A
Project Start
2007-09-01
Project End
2012-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
2
Fiscal Year
2008
Total Cost
$332,490
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
Lee, Naeun; Shin, Min Sun; Kang, Youna et al. (2016) Oligonol, a lychee fruit-derived low-molecular form of polyphenol mixture, suppresses inflammatory cytokine production from human monocytes. Hum Immunol 77:512-5
Shin, Min Sun; You, Sungyong; Kang, Youna et al. (2015) DNA Methylation Regulates the Differential Expression of CX3CR1 on Human IL-7R?low and IL-7R?high Effector Memory CD8+ T Cells with Distinct Migratory Capacities to the Fractalkine. J Immunol 195:2861-9
Lee, Naeun; You, Sungyong; Shin, Min Sun et al. (2014) IL-6 receptor ? defines effector memory CD8+ T cells producing Th2 cytokines and expanding in asthma. Am J Respir Crit Care Med 190:1383-94
Lee, Naeun; Shin, Min Sun; Kang, Ki Soo et al. (2014) Human monocytes have increased IFN-?-mediated IL-15 production with age alongside altered IFN-? receptor signaling. Clin Immunol 152:101-10
Shin, Min Sun; Lee, Jin Soo; Lee, Naeun et al. (2013) Maintenance of CMV-specific CD8+ T cell responses and the relationship of IL-27 to IFN-? levels with aging. Cytokine 61:485-90
Kang, Ki Soo; Lee, Naeun; Shin, Min Sun et al. (2013) An altered relationship of influenza vaccine-specific IgG responses with T cell immunity occurs with aging in humans. Clin Immunol 147:79-88
Shin, Min Sun; Kang, Youna; Lee, Naeun et al. (2013) Self double-stranded (ds)DNA induces IL-1? production from human monocytes by activating NLRP3 inflammasome in the presence of anti-dsDNA antibodies. J Immunol 190:1407-15
Kim, Jung-Sik; Cho, Bon-A; Sim, Ji Hyun et al. (2012) IL-7R?low memory CD8+ T cells are significantly elevated in patients with systemic lupus erythematosus. Rheumatology (Oxford) 51:1587-94
Lee, Won-Woo; Shin, Min Sun; Kang, Youna et al. (2012) The relationship of cytomegalovirus (CMV) infection with circulatory IFN-ýý levels and IL-7 receptor ýý expression on CD8+ T cells in human aging. Cytokine 58:332-5
Shin, Min Sun; Kang, Youna; Lee, Naeun et al. (2012) U1-small nuclear ribonucleoprotein activates the NLRP3 inflammasome in human monocytes. J Immunol 188:4769-75

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