Biology Reference
In-Depth Information
Figure 5.7. Mutated Tat proteins devoid of transactivating activity are as e½cient as wild-type
Tat proteins at inhibiting anti-IgM-mediated B-cell proliferation. Naive B cells were stimulated for
3 days by anti-IgM Ab and IL-4 in the presence of 1 mg/mL synthetic wild-type Tat proteins (Tat
MAL, Tat Eli) or synthetic Tat proteins mutated in their cystein±rich region (Tat Bru cmC, Tat
Oyi). Results of [
3
H]-thymidine incorporation are expressed in mean counts per minute (cpm) G SD
of triplicates determinations. Data are representative of ®ve independent experiments.
(E. A. Lefevre, personal communication). Kundu et al. showed that Tat pro-
longs the G1 cell cycle by decreasing the kinase activity of cdk2/cyclin E com-
plexes in glial cells ( Kundu et al., 1998), but the mechanism by which Tat
impairs B-cell progression is unknown. As Tat regulation of the proliferation of
naive/memory B cells di¨ers according to the stimulus used for their activation,
it may interact with speci®c cytoplasmic mediators or nuclear factors. Even if
added extracellularly, Tat is rapidly translocated into the nucleus, suggesting
that it is most likely to interact with nuclear mediators, such as NF-kB (Ru-
bartelli et al., 1998). The higher level of CD95 expression on anti-IgM-activated
naive and memory cells after treatment by Tat may favor their apoptosis
through CD95/CD95L interactions. In other respects, stimulation by CD40
mAb and IL-4 is a potent survival signal for GC B cells that leads to an in-
crease in the expression of Bcl-
xL
( Tuscano et al., 1996). It is thus possible that
Tat acts on GC B cells, in up-regulating the expression of these antiapoptotic
molecules. Alternatively, Tat may increase the expression of IL-4 receptors on
GC B cells, thereby increasing their sensitivity to IL-4 (Puri and Aggarwal,
1992). Whereas CD40 mAb and IL-2 plus IL-10 induce strong B-cell prolifer-
