Regulation of Telomere Length and Telomerase in T and B Cells

Recent studies have established that telomere length is altered during differentiation of both T and B lymphocytes. There exists a clear and strong correlation of replicative capacity with telomere length in normal somatic cells. In human T cells, this correlation extends to differences in telomere length and replicative capacity in subsets such as naive and memory CD4 cells, or CD28−positive and negative CD8 T cells. In addition, telomerase, a unique reverse transcriptase that is capable of extending telomeric length, is highly regulated during development and activation of both T and B lymphocytes. Together, these findings have provided a basis for hypotheses linking telomere length regulation to a functional role in sustaining the capacity for extensive clonal expansion in antigen-specific lymphocytes. In addition to providing insights into basic immune function, manipulation of telomere length has potential therapeutic applications as well. For example, the ability to extend the replicative capacity of cells such as hematopoietic stem cells or mature lymphocytes through telomerase induction by transfection could be critical to therapeutic approaches to adoptive cell transfer or reconstitution. In assessing the feasibility of such approaches, it will be critical not only to measure extension of the capacity for cell division but also to consider other possible consequences such as enhanced susceptibility to malignant transformation through dysregulated telomerase activity. Conversely, the proposed use of telomerase inhibition as a modality for anticancer therapy should consider the possible impact of such intervention on any telomerase-dependent aspects of immune function. The rapid pace of gene discovery and genetic engineering, in combination with a richness of available systems for studying immune cell biology, should allow vigorous pursuit of these remaining questions.‡To whom correspondence should be addressed (e-mail: Richard_Hodes@nih.gov).