Biology Reference
In-Depth Information
One of the newly identi®ed roles of CD28 is its involvement in the induction
of the enzyme telomerase. Telomerase is a specialized reverse transcriptase that
functions to extend telomere sequences at the ends of linear chromosomes. In
the absence of telomerase, telomeres, the repetitive DNA sequences on the ends
of chromosomes, shorten with each cell division (Harley et al., 1990). In tumor
cells, germ cells, and primordial stem cells, constitutive telomerase activity
presumably prevents telomere shortening and allows unlimited cell division
(Counter et al., 1994; Kim et al., 1994). This observation led to the theory that
telomerase activity was absent in all normal somatic cells and present only in
tumor cells. Indeed, extensive analyses of in vivo±derived tumor cell samples
con®rmed the presence of telomerase in >90% of tumors and its absence in
the adjacent normal cells from the same patient (Shay and Wright, 1996).
Telomerase activity, therefore, is believed to enable tumor cells to divide in-
de®nitely. Conversely, because telomerase is absent from most normal somatic
cells, it has been proposed that telomere shortening is causally linked to repli-
cative senescence ( Harley et al., 1990). However, it has recently become clear
that the relationship of telomeres, telomerase, and senescence is far more com-
plex in T lymphocytes than in other cell types.
Cells of the immune system di¨er dramatically from ®broblasts and most
other normal human somatic cells in that, under certain circumstances, they
exhibit telomerase activity levels similar to those observed in tumor cells. For
example, robust telomerase activity has been documented in tonsillar B cells,
developing T cells within the thymus, and in lymphoid organs (Weng et al.,
1996, 1997b). In addition, high levels of telomerase activity that correlate with
telomere length maintenance are observed in recently activated T cells (Bodnar
et al., 1996; Weng et al., 1997b). The activation-induced telomerase in T cells
is further enhanced by CD28 signaling ( Weng et al., 1996), and conversely,
telomerase up-regulation in antigen-speci®c human T cells can be blocked
by treatment of the APCs with antibodies that block the CD28/B7 interaction
( Valenzuela and E¨ros, 2000b). Interestingly, antigen-speci®c T cells that are
repeatedly reactivated by exposure to antigen over time in long-term culture
eventually lose the ability to up-regulate telomerase and senesce in culture
( Valenzuela and E¨ros, 2000b). If a similar down-regulation of telomerase in-
ducibility occurs in vivo, this could explain the presence of CD8 T cells with
shortened telomeres in situations of chronic antigenic exposure.
Telomere length measurement provides an extremely powerful tool for
analysis of both the replicative history and the future replicative potential of
most cells. In the absence of telomerase, telomere shortening occurs with each
cell division (Allsopp et al., 1992; Harley et al., 1990). Telomere analysis on cell
cultures of both ®broblasts and T cells has demonstrated that telomeres shorten
by approximately 100 bp per population doubling until reaching senescence
( Vaziri et al., 1993). The speci®c link between telomere length and cell cycle
arrest, the so-called telomere hypothesis of replicative senescence, was sup-
ported by several landmark studies published in early 1998. Speci®cally, it was
shown that in ®broblasts and pigmented retinal epithelial cells, the enforced
