Biology Reference
In-Depth Information
Isopenthenyl pyrophosphate is the precursor in the synthesis of a number
of important molecules including cholesterol and its derivatives (steroid
hormones, vitamin D, bile salts, lipoproteins), and in the synthesis of
terpenoids that modify signaling molecules in growing mammalian cells.
These metabolic intermediates are conserved between prokaryotic and
eukaryotic cells. Furthermore, the presence of IPP in mammalian cells
suggests that gd could potentially recognize autoantigens. It has been
proposed that either di¨erential concentration (higher in infected than
in noninfected cells) or di¨erential subcellular localization (cytoplasm
vs. phagosome) of IPP could explain gd T-cell discrimination between
infected and healthy cells. More recently, it has been hypothesized that
the basis of this discrimination between infected and noninfected cells is
the recognition of metabolic intermediates ( IPP precursors) that are
produced through a biochemical pathway exclusively present in bacteria
(Rohmer pathway) (Sicard and Fournie, 2000). The recently identi®ed 3-
formyl-1-butyl pyrophosphate is the favorite candidate as IPP precursor
to elicit speci®c gd T-cell activation and to target the response to infected
cells (Belmant et al., 1999b).
How phosphoantigens are recognized by gd TCR is not fully understood ( Fig.
8.1). Although intracellular processing may not be required, cell-surface
presentation and possibly extracellular processing may play a role in optimal
recognition of ligands by gd TCR (Belmant et al., 2000). Phosphoantigen rec-
ognition is TCRdependent and not restricted by MHC. Experiments with TCR-
blocking antibodies and TCR transfection of the Vg9Vd2 TCR cDNA into
TCR negative Jurkat cells have demonstrated involvement of the Vg9Vd2 TCR
in phosphoantigen recognition (Lang et al., 1995; Morita et al., 1995). Fur-
thermore, speci®city of prenylphosphate recognition seems to be conferred by
the combination of a particular CDR3 in the Vg9 chain and the Vd2 chain.
Thus, gd TCR junctional diversity may be responsible for di¨erentiating among
di¨erent phosphoantigens, and could be the basis for the discrimination be-
tween foreign and self-prenyl phosphates.
The existence of presenting molecules and cell-surface processing for phos-
phoantigens are issues that are still poorly understood (Fig. 8.1). Lack of re-
striction to known antigen-presenting elements (classical MHC class I or II and
nonclassical CD1a, 1b, or 1c) was demonstrated by use of de®cient mutant
cells, transfection experiments, and use of blocking antibodies (Tanaka et al.,
1994). Experiments with ®xed cells, TAP- or DM-de®cient cell lines, and TAP2-
de®cient patients demonstrated that antigen uptake and intracellular processing
by antigen-presenting cells (APC) were not required for gd T-cell activation by
phosphoantigens ( Fournie and Bonneville, 1996; Tanaka et al., 1994). Cell-cell
contact does appear to be required and the lack of evidence for direct binding
of the TCR to phosphoantigens (direct recognition) points toward the existence
of an as yet unknown presenting molecule. Moreover, reactivity to phospho-
antigens was lost by chemical substitution with nonhydrolyzable groups in
