Telomerase activity is up-regulated 1000-fold higher in human tonsil germinal center B cells compared to resting naive or memory B cells, and telomerase expression can be re-activated in vitro resting B cells. To understand the mechanism(s) of telomerase regulation, quiescent B cell from peripheral blood or tonsil were activated with different combinations of various stimuli. Cross-linking surface (s)IgD or sIgM of B cells induced marked up-regulation of telomerase enzymatic activity in the absence of cellular proliferation. Low level cross-linkage of surface molecules by soluble anti-IgM did not up-regulate the telomerase activity. However, the inability of soluble anti-IgM to up-regulate the telomerase activity was corrected by additional signals from soluble anti-CD40 antibody engagement or IL-4 / IL-10. Activation of B cell proliferation with Epstein-Barr virus failed to up-regulate telomerase, further suggesting that up-regulation of telomerase is an event independent of B cell proliferation. Telomerase induction occurred in the late G1 phase of the cell cycle and did not require entry into S phase. Up-regulation of telomerase enzymatic activity correlated primarily with the induction of expression of the hTERT gene, the catalytic subunit to telomerase, suggesting that control of telomerase regulation resides at the level of the catalytic subunit of this holoenzyme.