Investigating aging and membrane-associated T cell receptor signaling in human CD

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DESCRIPTION (provided by applicant): 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.