Biology Reference
In-Depth Information
fected donors ( Fiorentini et al., 1999; Posnett et al., 1999). However, in human
subjects, one can never conclusively prove that the CD28
ÿ
T cells arose by the
same mechanism. Nevertheless, the presence of identical HIV-speci®c clono-
types in the CD28
and CD28
ÿ
T cells has led several investigators to suggest
a common lineage for the two cell populations ( Dalod et al., 1999; Mugnaini
et al., 1998).
Functional studies provide additional evidence that is consistent with the
occurrence of replicative senescence during HIV disease progression. The pro-
liferative defects and apoptosis resistance, ®rst documented in cell culture, are
characteristic of ex vivo±derived CD28
ÿ
CD8
T cells from HIV-infected per-
sons (Posnett et al., 1999). Furthermore, when PBMC derived from HIV-
infected individuals are compared to PBMC that have been depleted of the
CD28
T cells, the precursor CTL ( pCTL) frequency for several HIV peptides
is the identical in the two cell populations ( Weekes et al., 1999b). Because
the removal of the T cells that express CD28 caused no reduction in the fre-
quency of pCTL, these studies demonstrate that the CD28
ÿ
T cells must be the
major source of the antigen-speci®c CTL function. As mentioned above, robust
antigen-speci®c cytolytic function is a hallmark of CD8 T cells that reach
replicative senescence in cell culture. Indeed, the antigen-speci®c cytotoxic
function of senescent cultures is even more potent than that of the CD28
T
cells from which they were derived (Perillo et al., 1993). Thus, CD28
ÿ
T cells,
whether generated in long-term cultures or tested ex vivo from HIV-infected
individuals, show speci®c proliferative defects, cannot be induced to express
telomerase activity, have telomeres of 5±7 kb, show potent antigen-speci®c
cytotoxicity, and are resistant to apoptosis, ®ndings that lend support to the
idea that the process of replicative senescence may be occurring within the CD8
T-cell subset during chronic HIV infection.
Elucidation of the nature and etiology of the CD28
ÿ
CD8
T cells that ac-
cumulate in HIV disease is not merely an academic exercise. Insight into the
origin of these cells will provide important information on both disease patho-
genesis as well as appropriate strategies for treatment. It is well-documented
that the CD8
T cells in HIV disease are a critical component of the protective
immune response (Borrow et al., 1994; Brodie et al., 1999; Koup et al., 1994).
Studies on long-term nonprogressors have highlighted the importance of CTL
function, and the loss of CD8 T-cell activity coincides with the progression to
AIDS (Cao et al., 1995; Goulder et al., 1997; Harrer et al., 1996). In addition
to this decrement and the limitation posed by CD28
ÿ
T cells on the process of
clonal expansion, because the CD28 molecule also functions to increase the
avidity of cell adhesion (Shimizu et al., 1992), cells lacking CD28 may have
altered tra½cking and homing patterns. Altered expression of other adhesion
molecules is, in fact, a feature of HIV disease ( Park et al., 1998; Schmitz et al.,
1998). Another functional characteristic of CD28
ÿ
CD8
T cells that might
impact disease progression is the altered generation of hydrogen peroxide as
well as catalase levels (Yano et al., 1998). Thus, the increasing proportion of
CD8 T cells that is hampered in its ability to undergo further clonal expansion,
