Abstract
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. Understanding the nature of the defects in these T-cells might facilitate intervention to improve immunity in the elderly. The process of clonal expansion under chronic antigenic stress can be modelled in vitro using continuously cultured T-cells. 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. Differentially expressed genes were confirmed by real-time polymerase chain reaction, and relationships between these assessed using Ingenuity Systems evidence-based association analysis. 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.
Highlights
The frequency of näive T-cells carrying receptors for a particular antigen is very low, so that in response to challenge, T-cell clones (TCC) must rapidly undergo numerous rounds of cell division in order to produce sufficient cells to cope with the antigenic insult
From work on infectious mononucleosis, it was estimated that about 28 population doublings were required for resolution of acute disease (Maini et al, 1999) agreeing remarkably well with estimates made on vaccinating cancer patients (Boon et al, 2006)
In order to examine the effect of in vitro culture-driven senescence on gene expression profiling, RNA samples from TCCs were isolated at various time points for microarray analysis (Table 1a)
Summary
The frequency of näive T-cells carrying receptors for a particular antigen is very low, so that in response to challenge, T-cell clones (TCC) must rapidly undergo numerous rounds of cell division in order to produce sufficient cells to cope with the antigenic insult. The absolute number of accumulated cells is an important part of the ‘immune risk profile’ (IRP) predicting mortality in longitudinal studies of the very elderly (Wikby et al, 2005). It is not just the number of cells, but the number of different expanded clones, which is associated with the IRP (Hadrup et al, 2006). Learning more about the reasons for accumulation of such dysfunctional cells may bring practical benefits in immune intervention in the elderly to reconstitute appropriate immune responses
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