ReviewSignaling pathways in aged T cells – A reflection of T cell differentiation, cell senescence and host environment
Highlights
► Mechanisms of TCR threshold calibration in T cell differentiation and aging are shared. ► The cytokine milieu in the aging host attenuates signaling cascades. ► The aging T cell is biased towards negative regulatory pathways. ► Negative regulatory receptors (ILT2, KIRs and KLRG1) interfere with pro-proliferative signals. ► Increased expression of dual-specific phosphatases attenuates MAP kinase pathways.
Introduction
Defects in signaling pathways involved in cell activation have been suspected to contribute to the declining immune function with age. In the current view, the T cell system is disproportionally affected by age [1] which leads to the failing efficacy of vaccination and the increased morbidity and mortality from viral infections such as influenza or the reactivation of chronic viral infections, e.g. in the form of herpes zoster [2], [3], [4], [5]. Regulation of signaling pathways is of utmost importance for T cell function. T cell receptor (TCR) signaling has to find the delicate balance between tolerating self-antigens and responding to foreign peptides. Costimulatory signals decide between effective response and anergy. And cytokine receptors regulate T cell proliferation and differentiation through various JAK-STAT pathways. It therefore does not come as a surprise that shortly after signaling components of the TCR pathway were identified, these were probed for abnormalities in aged mice [6]. TCR induced calcium influx was clearly diminished [7]. The underlying mechanisms have remained obscure; however, this defect appeared to account for the decreased IL-2 production, a hallmark for the immune aging of murine naïve T cells. Work by Miller and colleagues provided evidence for at least two mechanisms, both of which impaired or even prevented the formation of a T cell recognition platform [8]. T cells from aged mice had a defect in cytoskeletal organization on encountering antigen-presenting cells, at least in part independent of peptide recognition [9]. And, age influenced the glycosylation of cell surface molecules, in particular CD43, resulting in steric hindrance in the antigen recognition process [10], [11]. In addition, age-dependent alterations in plasma membrane lipids cholesterol-rich microdomains were implicated in defective T cell responses [12]. In contrast to murine T cells, findings in human T cells are more difficult to define and to interpret. Age-related alterations in human T cell responsiveness are more subtle, in particular, when T cells of similar differentiation status are compared [13]. The introduction of flow cytometry to measure signaling events has greatly enhanced our ability to quantify phosphorylated proteins, to examine several signaling events in phenotypically defined single cells and to perform high throughput analysis of larger populations, which is necessary given the inherent multifactorial variability in a human population. In this review, we will review age-related alterations in signaling pathways of human T cells. We will discuss how far age-related response patterns can be interpreted as progressive physiological T cell differentiation processes; what the contributions of adaptations to the aging host environment are; and how cell-internal senescence-associated mechanisms can influence signaling pathways. We will focus our discussion on the TCR receptor and the JAK-STAT pathways, the basic principles of which have been the subject of previous excellent reviews [14], [15].
Section snippets
TCR threshold calibration – essential for T cell development, detrimental for T cell aging
Calibration of TCR thresholds is an essential element in the life cycle of a T cell. Most notably, thymocytes have an exquisite TCR sensitivity which allows them to be positively selected on self-antigens. Sensitivity drastically changes with T cell maturation [16]. The naïve T cell that leaves the thymus is no longer able to respond to self-antigens with a productive response. Li et al. explored the signaling mechanisms that account for this rapid loss in TCR sensitivity and found a
Reactive oxygen species in aging and signaling
A popular model to explain aging is the free radical theory, where reactive oxygen species (ROS) are responsible for sustained damage to DNA, proteins and lipids. Mitochondria and NADPH oxidase are the major sources of ROS production in most cell types including T cells [23]. With increasing age, mitochondrial ROS leakage increases, mainly due to defective respiratory chain integrity [24], [25]. In addition to their harmful effects, ROS function as important physiological regulators of
T cell homeostatic cytokines and autoimmunity in aging
Signaling cascades are initiated in response to exogenous stimuli, frequently cytokines produced in the host. These signals lead to transcriptional activation of multiple genes, including gene products that are involved in positive and more often negative feedback loops of signaling pathways. Alterations in the host environment and in particular the cytokine milieu with age are predicted to modulate signaling pathways and in particular adjust the signaling thresholds at which productive
Age-dependent gene expression of molecules involved in signaling
Gene expression studies designed to identify the molecular basis for immunosenescence generally yielded cell surface receptors and cytoplasmic molecules involved in signaling processes topping the analysis (Fig. 2). Even before the era of gene arrays, loss of CD28 and CD27 and gain of several negative regulatory receptors including killer cell lectin-like receptor subfamily G (KLRG) and killer immunoglobulin-like receptors (KIR) were noted as hallmarks for cellular aging, in particular for CD8
Conclusions
There is increasing evidence to implicate altered signaling pathways in the immune defects seen with increasing age. In a recent study of in vitro replicative senescence of T cells, alterations in cell surface marker expression and TCR-induced signaling were highly predictive for CD8 T cell age. Rivet and colleagues used a microfluid chip analysis to quantify 25 static biomarkers and 48 dynamic signaling measurements [120]. A combination of Lck and ERK phosphorylation and cell surface
Acknowledgements
This work was supported by grants from the National Institutes of Health (U19 AI 57266 and U19 AI090019 to JJG, and R01 AR42527, R01 EY11916, R01 AI44142 and P01 HL058000 to CMW.
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