Regulation of telomerase activity in B cells
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Telomerase in the Immune System: The genomic information is stored in chromosomes within the cell nucleus and the ends of chromosomes in eukaryotes from yeast to mammals are capped by telomeres. These repetitive DNA sequences protect our genetic information but are faced with the predicament of getting progressively shorter with age through each cell division. Once telomeres have reached a critical minimum threshold, further divisions are curbed with the cell facing senescence. On the other hand, the enzyme telomerase consisting of the telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC) can counteract telomere shortening and elongate telomeres. This function is the canonical function of telomerase.
The expression of telomerase is highly restricted to germ cells and stem cells with very little expression in most adult cells apart from immune cells such as lymphocytes. This tight regulation is necessary as telomerase over-expression can result in cell immortalisation and abnormal tumorigenic proliferation. By contrast, telomere shortening due to loss of telomerase activity during terminal lymphocyte differentiation is associated with a decline of immune functions with age. The increased telomerase activity in subsets of activated immune cells is thought to protect lymphocytes from premature telomere erosion and senescence. However, recent work showed that engineered re-expression of telomerase in telomerase-deficient animals restored immune cell development without increasing telomere length, which suggest a non-canonical function for telomerase in immune cells, independent of its function on telomere elongation. Possible other functions of telomerase may relate to the regulation of cell survival and apoptosis.
The regulation of telomerase depends on highly cell-type-specific signals ranging from estrogen or leptin to brain-derived neurotrophic factor. Molecular mechanisms regulating telomerase activity in specific immune cells subsets are still only poorly understood to date. Like naïve T cells, naïve B cells have low levels of telomerase activity, in contrast to germinal centre B cells with high telomerase activity and longer telomeres. An early report has linked CD40-mediated signals to telomerase upregulation in activated B cells, yet it is unclear how naïve B cells regulate telomerase activity to maintain functionality over time.
In addition, as mentioned above telomere length does always correlate with telomerase activity in immune cells and there is increasing evidence published in high impact journals that non-canonical functions of telomerase have a key role in immune cells. Our laboratory has a project dissecting the non-canonical function of telomerase in immune cells and in particular B cells.
Professor Fabienne Mackay, Lab Head
Dr Asolina Braun, Postdoctoral Researcher
Professor Lea Harrington, Canada
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