Biology Reference
In-Depth Information
CD95L system and promoting nonprofessional CD95L-expressing killer cells,
which may be responsible for the destruction of CD95-expressing cells, abun-
dant in HIV-infected patients. Interestingly, experiments performed on lym-
phocytes from HIV-infected chimpanzees revealed that their resistance to CD4
T-cell depletion is associated with the lack of susceptibility of their T lympho-
cytes to CD95-induced apoptosis (Gougeon et al., 1997).
In addition to CD95L, other members of the TNF family are involved in
HIV-induced apoptotic cell death. We have recently shown that both CD4 and
CD8 T cells from HIV-infected persons are highly susceptible to TNF-RI and
also TNF-RII-mediated apoptosis (Fig. 12.1F ), and the molecular basis of this
process are currently under investigation. Apoptosis in CD8 T cells may involve
the TNF/TNF-R system inasmuch as in vitro binding of HIV gp120 on the che-
mokine receptor CXCR4, coreceptor for HIV, induces both the up-regulation
of membrane TNF on macrophages and TNF-RII on peripheral CD8 T cells,
leading to macrophage-dependent apoptosis of CD8 T cells ( Herbein et al.,
1998). The binding of HIV gp120 on CXCR4 also induces a rapid cell death in
normal CD4 T lymphocytes, independent of CD95, and inhibited by SDF-1
(Berndt et al., 1998). Finally, TRAIL (TNF-related-apoptosis-inducing-ligand)
was identi®ed as an apoptotic inducing factor on T cells from HIV-infected
patients, not on normal T cells (Katsikis et al., 1997).
Impact on Cytokine Synthesis
Upon antigenic activation, naive T cells proliferate and, according to the cyto-
kine environment and the nature of the costimulatory signals delivered by the
antigen-presenting cells, they can di¨erentiate into e¨ector cells with polarized
patterns of cytokine synthesis. Proin¯ammatory Th1 cells secrete IL-2, inter-
feron ( IFN )-g, and TNF-a, which are important mediators of cellular immu-
nity and are involved in activation of macrophages, whereas Th2 cells secrete
IL-4, IL-5, IL-6, IL-10, and IL-13, which provide help to B cells for immuno-
globulin (Ig) synthesis, mediate eosinophilia, and antagonize the macrophage-
activating action of Th1 cytokines. HIV-infection induces an early impairment
of cytokine synthesis because it is accompanied by a decline of in vitro pro-
duction of IL-2, IL-12, and IFN-g by peripheral blood mononuclear cells
(PBMCs) in response to recall antigens, an increased production of IL-4, IL-6,
and IL-10, and this Th1!Th2 shift is predictive for the reduction in CD4 cell
counts, time to AIDS diagnosis, and time to death (Clerici and Shearer, 1994).
To study the possible impact of apoptosis on alteration in cytokine synthesis,
we have developed a single-cell analysis method that allows enumeration of
Th1/Th2 subsets derived from polyclonally short-term stimulated peripheral T
cells and concomittant analysis of their priming for apoptosis ( Lecoeur et al.,
1998). With that approach and under the experimental conditions used (16-h
stimulation of PBMC with PMA ionomycin), we found that HIV infection is
associated with a di¨erential alteration in the representation of Th1 subsets,
rather than a commitment of T cells to secrete Th2 cytokines (Ledru et al.,
