Biology Reference
In-Depth Information
typhimurinum, Yersinia enterocolitica), and intracellular bacteria (Mycobacte-
rium tuberculosis, Mycobacterium leprae) ( Fournie and Bonneville, 1996). Soon
after the observation was made that Vg9Vd2 T cells have broad reactivity to
infectious agents, the search for microbial antigens was begun. The ®rst can-
didate antigens were the heat shock proteins, because the HSP 65 was deter-
mined to be a potential major stimulus for murine gd T cells (Born et al., 1990).
However, it was soon evident that peptidic antigens were not the most common
stimulatory molecules for human gd T cells and gd antigenic speci®cities strik-
ingly diverged from conventional ab T-cell antigens. The original observation
that gd stimulatory antigens were of low molecular mass and protease resistant
came from studies of gd T-cell responses to mycobacterial antigens (Pfe¨er et
al., 1990, 1992). Two approaches were undertaken to characterize these mole-
cules, puri®cation from mycobacterial sources and assays with synthetic com-
pounds. In 1994, two groups separately reported the chemical features of the
nonpeptidic gd stimulatory antigens (Constant et al., 1994; Tanaka et al., 1994).
The common feature of these compounds was the presence of phosphate
groups. These nonpeptidic compounds with phosphoester structures that stim-
ulate gd T cells are collectively called ``phosphoantigens.'' Subsequent studies
by these two groups suggested that there are two classes of phosphoantigens:
1. Nucleotide-conjugated compounds (isopentenyl-ATP, TUBAg3-4). The
TUBags were puri®ed from mycobacterial lysates and are found in the
cytosolic fractions (Constant et al., 1994, 1995; Lang et al., 1995; Poquet
et al., 1996a, b). They are g-derivatives of uridine triphosphate (X-gUTP)
and thymidine triphosphate (X-gTTP). The identity of the X moiety
was recently reported by Belmant et al. as being 3-formyl-1-butyl-
pyrophosphate, which resembles and likely is related to isopentenyl
pyrophosphate (IPP) (Belmant et al., 1999b). These TUBag compounds
have been shown to be active in the nanomolar range (1000-fold more
reactive than IPP), and the authors suggest that they could account for
most of the gd T-cell-stimulating activity recovered from mycobacteria.
2. Pyrophospho- and phosphomonoesters (IPP, monoethylpyrophosphate
or MEPP, 2,3 diphosphoglycerate, glycerol 3-phosphate, TUBag1-2, and
MALAg 1-2). IPP was isolated from mycobacteria (Mycobacterium
fortuitum, Mycobacterium smegmatis) extracts and culture ®ltrates and
described as the ®rst structurally identi®ed natural ligand for human gd
T cells (Morita et al., 1995; Tanaka et al., 1994, 1995, 1996). Observa-
tions by Morita et al. (Morita et al., 1999) also indicate IPP synthesis by
E. coli, and Y. enterocolitica. A related compound was also identi®ed in
P. falciparum and is called MALAg. Vg9Vd2 T cells are also reactive to
surface antigens on human B-cell tumors ( Daudi cells). However, the re-
lationship between phosphoantigens and ``tumor antigens'' for gd T cells
has not yet been clari®ed. The explanation for the broad reactivity of gd T
cells to a variety of microorganisms and tumor cells could be the recog-
nition of the ubiquitous metabolites such as the prenyl pyrophosphates.
