MECHANISMS REGULATING TELOMERASE ACTIVITY IN MURINE T-CELLS

Telomeres shorten with successive cell divisions in normal somatic cel ls, while telomerase plays an important role in maintaining their leng ths. Although telomerase activity was originally described as being ex pressed exclusively by immortal cells and germline cells, a recently d eveloped PCR-based technique (telomeric repeat amplification protocol (TRAP)) has revealed that normal peripheral blood leukocytes also exhi bit this activity following mitogenic stimulation, in this study, we e xamined mechanisms by which mitogenic stimuli up-regulated telomerase activity in T cells. Splenic T cells freshly isolated from BALB/c mice exhibited only negligible telomerase activity. When stimulated with C on A or immobilized anti-CD3 mAb at 10 mu g/ml, they acquired an incre ased telomerase activity and maximal proliferation, By contrast, T cel ls treated with a much lower concentration (0.03 mu g/ml) of anti-CD3 mAb required exogenous IL-2 for telomerase activation and proliferatio n. Likewise, adult thymocytes treated with anti-CD3 mAb exhibited telo merase activation and proliferation only in the presence of exogenous IL-2, IL-4, IL-7, or IL-15. Furthermore, IL-2 alone was sufficient for telomerase activation in Con A blasts. These results illustrate a pat hway through which cytokine receptors transduce telomerase activation signals in T cells. Although telomerase activation was concomitant wit h cell growth in normal T cells, we have identified T cell lines that showed discrepancies; the CTLL-2 line showed constitutive telomerase a ctivity regardless of cell proliferative state, whereas the 7-17 line proliferated vigorously in response to IL-2, IL-7, or IL-15, without d etectable telomerase activity. Thus, telomerase activity, which is ord inarily associated with proliferation in normal T cells, is not necess arily required or sufficient for cell growth.