Alterations in T cell immunity occur with aging, contributing to increased risk of infection and malignancy. T cells are activated as they recognize antigenic peptide presented by antigen-presenting cells (APCs) via T cell receptors (TCR). This TCR triggering induces a series of biochemical events called signal transduction in T cells which are essential for T cell functions. Of interest, age-associated alterations in TCR signal transduction have been reported in mice and humans, linking to impaired T cell functions. However, in most human studies unsorted total CD4+ or CD8+ T cells have been used although different CD4+ and CD8+ T cell subsets, such as na?ve and memory cells, with distinct functions exist and the proportion of na?ve and memory CD4+ and CD8+ T cells alters with aging. Recently, my lab measured expression of IL-7 receptor alpha chain (IL-7Ra, CD127) which dictates the response to IL-7, a cytokine critical for T cell homeostasis, on CD8+ T cells in young and elderly individuals. In this study, cells expressing IL-7Rahigh and low were found in memory CD8+ T cells. Surprisingly, the elderly (age=65) had expansion of IL-7Ralow memory CD8+ T cells compared to the young (age=40). IL-7Ralow memory CD8+ T cells poorly proliferated in response to TCR triggering, indicating a TCR signaling defect(s) in these cells and the potential role for IL-7Ra as a marker for identifying memory CD8+ T cells with impaired TCR responses. Of interest, IL-7Ralow memory CD8+ T cells nicely proliferate in response to a combination of TCR triggering and IL-15, a cytokine essential for memory CD8+ T cell maintenance. This suggests a role for IL-15 in recovering the impaired TCR signal transduction in IL-7Ralow memory CD8+ T cells. Understanding the mechanism(s) for these findings is important since memory CD8+ T cells are essential for host defense and IL-15 is considered as an adjuvant for cellular immunity. The proposed study will address these issues based on the hypothesis that expanded IL-7Ralow memory CD8+ T cells with aging have a defect(s) in TCR signal transduction which can be rescued by IL-15. This hypothesis will be investigated focusing on a group of TCR signaling molecules that are closely associated with T cell membrane using confocal microscopy and flow cytometry. Specifically, following two aims are planned. First, investigate whether and why IL-7Ralow memory CD8+ T cells that expand with aging have a defect(s) in TCR signal transduction. Plus, alteration(s) in TCR signal transduction of other CD8+ T cell subsets and the potential mechanisms for defective TCR signal transduction in the CD8+ T cell subsets will be studied by measuring cholesterol content of the cell membrane and glycosylation of T cell surface molecules that are known to affect TCR signal transduction with aging. Secondly, it will be determined how IL-15 rescues impaired TCR signal transduction in IL-7Ralow memory CD8+ T cells. The results of this study will provide essential information that leads to better protection against tumors and infections in the elderly by enhancing cellular immunity. The goal of the current proposal is to study how aging affects the molecules involved in transmitting stimulations from the outside to the inside (signal transduction) of CD8+ T cells through their receptors (T cell receptor). The results of this study will provide important information on enhancing immune responses in the aged populations, leading to improved protection against infections and tumors. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AG030834-01
Application #
7330276
Study Section
Special Emphasis Panel (ZAG1-ZIJ-2 (M1))
Program Officer
Fuldner, Rebecca A
Project Start
2007-09-01
Project End
2009-06-30
Budget Start
2007-09-01
Budget End
2008-06-30
Support Year
1
Fiscal Year
2007
Total Cost
$135,300
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
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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
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
Lee, Naeun; Shin, Min Sun; Kang, Insoo (2012) T-cell biology in aging, with a focus on lung disease. J Gerontol A Biol Sci Med Sci 67:254-63
Lee, Jin Soo; Lee, Won-Woo; Kim, Sang Hyun et al. (2011) Age-associated alteration in naive and memory Th17 cell response in humans. Clin Immunol 140:84-91
Shin, Min S; Lee, Naeun; Kang, Insoo (2011) Effector T-cell subsets in systemic lupus erythematosus: update focusing on Th17 cells. Curr Opin Rheumatol 23:444-8
Shah, Kamini; Lee, Won-Woo; Lee, Seung-Hyun et al. (2010) Dysregulated balance of Th17 and Th1 cells in systemic lupus erythematosus. Arthritis Res Ther 12:R53
Lee, Won-Woo; Kang, Seong Wook; Choi, Jihoon et al. (2010) Regulating human Th17 cells via differential expression of IL-1 receptor. Blood 115:530-40

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