A hallmark of aging in both humans and rodents is thymic involution or decrease in thymic mass. Although this suggests that the ability of the thymus to produce new naive T-cells decreases in combination with decreased progenitor production in the bone marrow, it would be predicted that peripheral T-cell numbers should decline with age. However, the impact on peripheral T-cell number appears to be minimal. This may be due to clonal expansion of mature memory and naive T-cells in the periphery. The spleen is one of the major secondary lymphoid tissues, and aging appears to reduce germinal center (GC) size by as much as 90%, as determined based on size and cellularity. The decrease in GC size, which may result in decreased B cell activation and subsequent proliferation, may be responsible for the decrease in plasma B cells. Recent evidence demonstrated that the decline in proliferation in the GC is due to the lack of costimulatory signals provided by T cells located in the surrounding tissue (Zheng et al., 1997).
Aging also results in dysregulated humoral immunity, which may be due to defects in B cells directly and T cell help indirectly. Two problems in B cell development have been found in aged mice. First, the generation of pre-B cells from pro-B cells is two-fold less in aged mice (Klinman and Kline, 1997), which may be due to decreased RAG gene expression in B cell precursors
(Ben-Yehuda et al., 1994). Second, the generation of sIgM+ B cells from sIgM- B cells is reduced by aging. The net result is an accumulation of sIgM- B cells and subsequent reduction in mature B cell formation. Altogether, the rate of mature B cell generation is only 20% in old mice as compared to young mice (Klinman and Kline, 1997). However, the total peripheral B cell number is normal in aged mice, which may be due to a slower turnover rate (i.e., longer lifespan) of mature B cells in the aged (Klinman and Kline, 1997). B cells that do reach maturity in aged mice also have defects. For example, some aged B cells have defects in Ig gene rearrangement, specifically V gene repertoire formation, which has been shown to result in hyper B cell reactivity to phosphorylcholine (Riley et al., 1989). The net result of these age-associated defects in B cell development is a decreased response to foreign antigen and a shift from IgG to IgM predominance (LeMaoult et al., 1997). Paradoxically, autoantibody production increases in old mice and humans. This may be due to the indirect actions of the help B cells receive from autoreactive T cells that may be increased with age (Klinman and Kline, 1997; LeMaoult et al., 1997).
Although in both humans and mice, the total number of peripheral T cells doesn't change significantly with age, a decrease in T cell subpopulations does occur. Commonly, a decrease in naive T cell numbers and a concomitant rise in memory T cells are seen in aged rodents and humans. The increase in memory T cell proportions correlates with reduced polyclonal T cell proliferation ex vivo in response to a wide variety of mitogens like anti-CD3 and concanavalin A in humans and rodents. Two major changes in aged T cells have been found in humans, which may explain the reduced proliferation. First, CD28 receptor expression is decreased on human, but not rodent, T cells. Approximately 99% of the T cells from newborn humans express CD28, which decreased to 85% in adults and further decreases with age to 50 to 70% in the elderly (Effros, 1996). Second, CD95 receptor expression also declines. In young T cells, CD95 expression will increase upon stimulation, preventing T cells from proliferating out of control by inducing apoptosis (Aspinall et al., 1998). In aged T cells, the increase in CD95 expression and subsequent induction of apoptosis do not occur in response to stimulation ex vivo, suggesting that there is a defect in T cell deletion following a normal immune response (Herndon et al., 1997).
As mentioned before, anti-TCR or anti-CD3 mAb treatment on resting T cell could initiate a series of activation of protein kinases and an increase of Ca2+ concentration, which contribute to the activation of transcription factors, secretion of cytokines, and cell proliferation. In old mice, CD4+ T cells lose the ability to robustly increase intracellular Ca2+ concentrations in response to stimulation. It seems that this phenomenon is independent of IP3 production and function, but related to high levels of Ca2+ extrusion and a low level of Ca2+
release from the intracellular pool (Miller et al., 1997). Similar to the calcium signal, phosphorylation signals in T cell activation are different in old mice. More specifically, the extent of CD3y chain phosphorylation is much weaker in old T cells. This decreased phosphorylation of CD3y chain reflects a combination of decreased kinase activity, increased phosphatase activity, and increased difficulty to access the TCR/CD3 complex (Miller et al., 1997). Downstream, other protein kinases such as Raf-1, MEK, and ERK show age-associated decline in activity upon stimulation (Miller et al., 1997). Recently, the function of negative regulators in T cell signal transduc-tion pathways and its effects on aging are beginning to be examined. For instance, Cbl-b, an E3-ubiquitin ligase, can bind with both CD3 and CD28 upon cell stimulation and consequently associate with various proteins that are essential to signal transduction (Bachmaier et al., 2000). In contrast to the positive regulator that enhances the stimulatory signals, Cbl-b can catalyze the ubquitination of the associated signaling proteins and down-regulate protein function by either sending them to the proteasome for degradation or blocking the association of substrate proteins with other effector protein in a proteasome-independent mechanism (Xu et al., 2004). Thus, Cbl-b can set the threshold of T cell activation. Cbl-b itself can be down-regulated upon T cell stimulation in young T cells, and such proteasome-mediated degradation is missing in old T cells. Thus, in old T cells, a stronger negative regulation form Cbl-b persists upon stimulation, and T cell activation is diminished in old T cells (Xu et al., 2004). As a result of reduced T cell activation, IL-2 production is reduced, and a dysregulation of T helper cell function results, which may impact B cell, CD8+ T cell, and other accessory cells in old rodents.
A significant proportion of aging immune research has focused on the CD4+ T helper cells because of its functional importance in regulating both humoral and cell-mediated immunity. Recently, changes in CD8+ T cytotoxic cells have also been found to occur in aging, and examination of both T cell subsets will be important in understanding immune senescence. For example, up to 70% of CD8+ T cells in aged rodents express an identical TCR gene, indicating they are derived from same-parent CD8+ T cells. These types of CD8+ T cells are called large CD8 T cell clones and have a poor proliferate capacity in both human and mouse (Ku et al., 1997). The reason for the large CD8+ T cell clones is most likely due to frequent exposure to the same antigen, which is most likely to occur on old rodents and humans (Ku et al., 1997).
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