Telomerase is up-regulated in human germinal center B cells in vivo and can be re-expressed in memory B cells activated in vitro.

Abstract

The extensive proliferation that B lymphocytes undergo in germinal centers could compromise generation of long term B cell memory if there occurs shortening of the telomeres of germinal center B cells with cell division. Telomere length, which is thought to act as a "mitotic clock" for somatic cells that dictates cellular senescence, can be preserved by the enzyme telomerase. Human tonsil germinal center B cells consistently expressed 100- to 1000-fold higher levels of telomerase activity than naive or memory B cells, which had no or very low detectable activity, as analyzed by the telomere repeat amplification protocol assay. In vitro stimulation of human memory B cells through surface Ig or CD40 was capable of up-regulating telomerase. The findings suggest that longevity of B cell memory is maintained, despite multiple cell divisions in the generation of a memory B cell, by up-regulation of telomerase in germinal center and activated memory B cells.

Human anti-smallpox long-lived memory B cells are defined by dynamic interactions in the splenic niche and long-lasting germinal center imprinting

“…None of these enzymes, apart from NHP2, appeared significantly over-expressed at the mRNA level in resting MBCs in our scRNA-seq dataset (Figure 7A). In contrast, strong expression of numerous members of the shelterin (dedicated to structure and protection of telomeres (de Lange, 2018)) and telomerase complex could be detected in actively dividing GC B cells, in line with the previously described telomerase activity in GC B cells (Hu et al, 1997;Martens et al, 2002;Norrback et al, 2001;Weng et al, 1997). TERT transcripts could not be detected in any of the assayed cell types in our scRNA-seq dataset.…”

“…This slow erosion also favors a model in which early elongation at the naive to memory differentiation step, rather than periodical reactivation of telomerase throughout life, accounts for the telomere size seen in IgG + switched MBCs. Strong telomerase activity in GC B cells has been reported but results regarding whether this leads to elongated telomeres in generated MBCs were still controversial (Hu et al, 1997;Martens et al, 2002;Norrback et al, 2001;Son et al, 2003;Weng et al, 1997). Our data strongly suggest that the passage in GCs provides GC-derived MBCs with a reserve in telomere provision, in the 10-15kb range.…”

Proliferative History Is a Novel Driver of Clinical Outcome in Splenic Marginal Zone Lymphoma

“…Our analysis suggests that epiCMIT, accumulated gradually and consistently during B cell differentiation, emerges as a more clinically relevant biomarker compared to TL. Unlike TL, which does not exhibit a linear decrease and instead shows a marked increase in germinal center-derived B-cells due to transient telomerase upregulation (36), epiCMIT’s consistent accumulation makes it a more robust biomarker. Like chronic lymphocytic leukemia (CLL), proliferation leading to telomere shortening may provide SMZL cells with a survival advantage by inducing genomic instability, driving further clonal evolution and disease progression (37, 38).…”

Integrative epigenomics in chronic lymphocytic leukaemia: Biological insights and clinical applications

“…The epiCMIT is accumulative and gradually increases during B‐cell maturation 39 . In the case of telomere length, it does not linearly decrease as B cells proliferate and differentiate, but sharply increases in GCBCs (due to transient telomerase upregulation 45 ) as compared to naïve and memory B cells, which show similar telomere lengths when sorted from peripheral blood 46 . Therefore, in principle, we would not expect U‐CLLs and M‐CLLs to have different cell of origin‐related telomere lengths.…”