Biology Reference
In-Depth Information
easily identi®able characteristic of replicative senescence, it is just one of a
constellation of features associated with this cell state. T cells that have reached
replicative senescence still retain some normal functions despite their inabil-
ity to proliferate. For example, senescent CD8 T cells are capable of normal
antigen-speci®c cytotoxic function and upregulation of CD25 (the alpha chain
of the interleukin [IL]-2R) surface expression ( Perillo et al., 1993). Similarly,
senescent CD4 T cells secrete certain cytokines after stimulation via their anti-
gen receptors in an antigen-speci®c fashion. Evidence has also been forth-
coming for the acquisition of certain other properties and functions, including
major histocompatibility complex (MHC, unrestricted cytotoxicity or natural
killing), negative regulatory e¨ects on other T cells (suppression), and expres-
sion of the CD4 receptor on CD8 T cells, making them double positive ( Laux
et al., 2000; Pawelec et al., 1986). Thus, senescence does not constitute a general
breakdown of normal function, but rather may comprise selected genetic and
phenotypic alterations, resulting not only in loss, but also in gain, of function.
It has been proposed, therefore, that replicative senescence may, in fact, repre-
sent a developmentally programmed state of terminal di¨erentiation in T cells
(Globerson and E¨ros, 2000).
Several important genetic changes are associated with T-cell replicative
senescence in cell culture. For example, CD8 T-cell senescence is associated
with increased expression of bcl 2 and resistance to apoptosis (Spaulding et al.,
1999), changes that have also been observed in cultures of senescent ®broblasts
(Wang et al., 1994). Another genetic feature associated with replicative senes-
cence in T cells is the dramatically reduced transcription of gene for the major
heat shock protein, HSP70, in response to stress (E¨ros et al., 1994b). Argu-
ably, the most dramatic change associated with T-cell replicative senescence in
cell culture is the complete loss of cell surface (and mRNA) expression of the
CD28 costimulatory molecule ( E¨ros et al., 1994a; Pawelec et al., 1997). The
complete absence of CD28 on the cell surface at senescence is in marked con-
trast to the quantitative modulation in the level of CD28 expression that ac-
companies the process of activation. The loss in CD28 expression in cultures
that reach replicative senescence is also remarkable in light of the unchanged
expression of a variety of other T-cell markers re¯ecting lineage, activation,
memory status, and adhesion (Perillo et al., 1993).
CD28 is a 44-kD disul®de-linked homodimer expressed constitutively on
the majority of mature T cells whose signaling is essential for full T-cell acti-
vation. Ligation of the T-cell antigen receptor without costimulation by CD28
ligands such as the ``B7'' proteins on the surface of antigen-presenting cells
(APCs) results in anergy, an unresponsive state in which the cells are unable to
enter cell cycle. CD28 signal transduction results in IL-2 gene transcription,
expression of the IL-2 receptor, and the stabilization of a variety of cytokine
messenger RNAs (June et al., 1994). CD28 has additional biologic functions,
which include mediation of protective e¨ects against septic shock in vivo,
in¯uencing the class of antibodies produced by B cells, and enhancing T-cell
migration and homing (Shimizu et al., 1992).
