All cells change over the course of the aging process, but we pay special attention to immune cells for several reasons:

  1. Samples can be easily obtained (via blood draw) for manipulation in vitro;
  2. Immune surveillance is an important component of the body’s defense against cancer throughout the lifespan; and
  3. Immune cells are everywhere (except the brain, generally), so immune function is pertinent to the function of all tissues.

Here are two abstracts pertaining to different aspects of T cell aging. First, Mazzatti et al. discuss the changes in gene expression associated with T cell senescence, a process that occurs when the natural shrinking of T cell clones after infection goes awry. The authors find that gene expression underlying several key signaling pathways are systematically altered as T cells approach senescence (emphasis mine):

The adaptive immune response requires waves of T-cell clonal expansion on contact with altered self and contraction after elimination of antigen. In the case of persisting antigen, as occurs for example in cytomegalovirus or Epstein–Barr virus infection, this critical process can become dysregulated and responding T-cells enter into a dysfunctional senescent state. Longitudinal studies suggest that the presence of increased numbers of such T-cells is a poor prognostic factor for survival in the very elderly. … Here, we have used cDNA array technology to investigate differences in gene expression in a set of five different T-cell clones at early, middle and late passage in culture. … Several genes and chemokines related to induction of apoptosis and signal transduction pathways regulated by transforming growth factor β (TGFβ), epidermal growth factor (EGF), fos and β-catenin were altered in late compared to early passage cells. These pathways and affected genes may play a significant role in driving the cellular senescent phenotype and warrant further investigation as potential biomarkers of aging and senescence. These genes may additionally provide targets for intervention.

A possible mechanism for some age-related transcriptional changes is provided by Das et al., who describe the negative effect of oxidation (both experimental and age-related) on the proteasome. The proteasome disposes of unwanted proteins, usually marked for degradation by polyubiquitination. More than just a cellular trash can, the proteasome plays an important role in regulatory biology by degrading transcriptional activators and inhibitors, e.g., IκBα, the inhibitory partner of the transcription factor NFκB:

Proteasome is a major cellular organelle responsible for the regulated turnover of both normal and misfolded proteins. Recent reports from our laboratory have implicated lowered proteasomal chymotryptic activity to be responsible for decreased induction of the transcription factor NFκB in T lymphocytes during aging. In this study, we have further analyzed the basis for this decline in proteasomal function, by focusing on the role of oxidative stress. On exposure to the prooxidant BSO, both ATP-stimulatable 26S and ATP-independent 20S proteasomal catalytic activity could be down-regulated in T cells from young donors, mimicking the decline observed in T cells from the elderly. Loss in these catalytic activities, following exposure to prooxidant stimulus, also resulted in a decline in both activation-induced proliferation and degradation of the inhibitor IκBα, with concomitant increase in the accumulation of carbonylated proteins, mimicking responses seen in T cells from the elderly. … These results suggest that the decrease in proteasomal activities observed during aging may be secondary to oxidative stress and underlie immune senescence.

Both studies are excellent examples of the experimental versatility of T cells, which allow investigators to construct in vitro models that recapitulate the essence of interesting phenomena occurring in vivo.