Biology Reference
In-Depth Information
tion. Although there had been much speculation by AIDS researchers on the
origin of the CD28
ÿ
T cells, elucidation of the nature of this expanded popu-
lation of cells in HIV disease has emerged from research in a totally di¨erent
arena of scienti®c investigation, namely basic cell biology studies on the process
of replicative senescence. This chapter will review the ®ndings that have led to
the unexpected convergence of these two seemingly unrelated ®elds.
REPLICATIVE SENESCENCE
Normal human somatic cells have an intrinsic natural barrier to unlimited cell
division. Following a fairly predictable number of cell divisions in culture,
most, if not all, mitotically competent human cells reach an irreversible state of
growth arrest known as replicative senescence, a process ®rst identi®ed by
Hay¯ick in human fetal ®broblasts ( Hay¯ick, 1965). Replicative senescence is a
strict characteristic of human cells, and has, in fact, been proposed to constitute
a tumor suppressive mechanism (Smith and Pereira-Smith, 1996). Interestingly,
experimental cell fusion studies have demonstrated that the property of senes-
cence is genetically dominant over immortality in a variety of human cell types,
and spontaneous transformation of human cells in vitro rarely, if ever, occurs
(Smith and Pereira-Smith, 1996). By contrast, most rodent cells have a high
propensity to bypass senescence and transform spontaneously in culture (Cam-
pisi et al., 1996). The divergent behavior of human and mouse cells with respect
to spontaneous immortalization in vitro suggests that conclusions regarding
replicative properties, telomeres, and telomerase drawn from murine studies
may not be applicable to human cells.
The characteristics of replicative senescence, or the so-called Hay¯ick Limit,
have been explored in a variety of human cell types for more than 30 years, but
only relatively recently has this model been applied to the immune system.
Ironically, the Hay¯ick Limit may be particularly deleterious for immune cells,
inasmuch as the ability to undergo rapid clonal expansion is absolutely essential
to their function.
During the past decade, human T cells have been extensively characterized
in cell culture models with respect to replicative senescence. A number of large-
scale studies have shown that following multiple rounds of antigen, mitogen, or
activatory antibody-driven proliferation, T cells reach a state of growth arrest
that cannot be reversed by further exposure to antigen, growth factors, or any
other established T-cell stimuli (E¨ros and Pawelec, 1997). The occurrence of
replicative senescence has been documented for both clonal and bulk cultures
of CD4 and CD8 T cells (Adibzadeh et al., 1995; Grubeck-Loebenstein et
al., 1994; McCarron et al., 1987). It has also been shown that the replicative
potential of memory CD4 T cells is reduced compared with naÈve CD4 T cells
from the same individual, a ®nding that is consistent with the notion that
memory cells are the progeny of antigen-stimulated naÈve T cells ( Weng et al.,
1995). It is important to emphasize that although cell cycle arrest is the most
