Gene expression changes in long-term culture of T-cell clones: genomic effects of chronic antigenic stress in aging and immunosenescence.
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 beta (TGFbeta), epidermal growth factor (EGF), fos and beta-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.
Mazzatti
Dawn J
DJ
Unilever Corporate Research, Colworth Park, Sharnbrook, Bedford MK44 1LQ, UK. dawn.mazzatti@unilever.com
White
Andrew
A
Forsey
Rosalyn J
RJ
Powell
Jonathan R
JR
Pawelec
Graham
G
D000369:Aged, 80 and over; D000941:Antigens / Q000276:immunology; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics*; D017635:Clonal Anergy / Q000235:genetics; D002999:Clone Cells; D015870:Gene Expression; D053263:Gene Regulatory Networks; D015894:Genome, Human; D006801:Humans; D013601:T-Lymphocytes / Q000276:immunology*
D000941:Antigens