REGULATION OF LYMPHOCYTE PROLIFERATION AND REPLICATIVE CAPACITY

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The replicative history and replicative potential of human naive and memory T cells, critical parameters of lymphocyte biology, were analyzed. Telomeres are unique terminal chromosomal structures which shorten with cell division in vitro and with increased age in vivo for human somatic cells. We assessed telomere length as a measure of the in vivo replicative history of naive and memory human T cells, and found that telomeric terminal restriction fragments were 1.4 q 0.1 kb longer in CD4+ naive T cells than in memory cells from the same donors, a relationship that was constant over a wide range of donor age. This suggests that the differentiation of memory cells from naive precursors occurs with substantial clonal expansion that is similar over a wide age range. The in vitro replicative capacity of naive cells was 128-fold greater than that of memory cells from the same donors. Human CD4+ naive and memory cells thus differ in in vivo replicative history as reflected in telomeric length as well as in their residual replicative capacity. These relationships may be significant for pathologies such as HIV infection, in which CD4+ T cell generation may be compromised, and for therapeutic interventions mediated by cells whose in vivo expansion is essential for therapeutic effect. Analysis of telomere length regulation in human B cells demonstrated that germinal center(GC)B cells have significantly longer telomeres than the naive B cells that are their precursors or the memory B cells that are their progeny. These results suggest the novel possibility that normal somatic cells of the B lymphocyte lineage express a mechanism capable of extending telomere length. Such a mechanism might function to extend the capacity for clonal expansion of memory and effector B cells. Telomerase, a ribonucleoprotein enzyme that is capable of synthesizing telomeric repeats, is expressed in germline and malignant cells and is absent in most normal human somatic cells. The selective expression of telomerase has thus been proposed to be a basis for the immortality of the germline and of malignant cells. When telomerase activity was analyzed in normal human T lymphocytes, it was found that telomerase is expressed at a high level in thymocytes, at an intermediate level in tonsil T cells, and at a low to undetectable level in peripheral blood T cells. Moreover, telomerase activity was highly inducible in peripheral T lymphocytes by activation through CD3 and CD28 (anti- CD3/CD28). Telomerase may thus play a permissive role in T cell development and in determining the capacity of lymphoid cells for clonal expansion. In differentiating human tonsil B cells, it was demonstrated that telomerase is expressed specifically at a high level in GC B cells. Expression of telomerase in these cells may provide a mechanism for the apparent telomere lengthening that occurs in differentiation from precursor to GC B cells. A model system has been established for analysis of the genetic regulation of telomere length in mice. Inter-fertile species of mice were identified which differ significantly in telomere length. Crosses between these species have in initial experiments demonstrated that 1) a mechanism exists for substantial telomere lengthening in somatic cells in vivo, and 2) that species-specific telomere length is regulated by segregating genes that are polymorphic between these species.