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T Cells by Nonpeptide Antigens1
Department of Immunology and Cell Biology, Graduate School of Biostudies, and Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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2/V
2+ T cells respond to low
molecular-mass nonpeptide Ags in a TCR-dependent manner.
Although requirements of Ag presentation have remained controversial,
we have indicated that specific responses of the primary T cells
to pamidronate were dependent on monocytic adherent cells for Ag
presentation. Here, we show that human tumor cells can efficiently
present aminobisphosphonate and pyrophosphomonoester compounds to
T cells, inducing specific proliferation and IFN- production.
TCR dependency of the response to Ag-pulsed tumor cells was
confirmed by using a Jurkat line transfected with a V2/V2
TCR. Furthermore, T cells exhibited markedly enhanced
cytotoxicity against the Ag-pulsed tumor cells as compared with
untreated tumor cells. Survey of a number of human tumor cell lines of
different origins revealed that the majority of them became susceptible
for T cell-mediated cytotoxicity following the Ag pulsing except
for breast cancer lines so far examined, while normal PHA blast cells
remained resistant. The results not only imply a unique mode of
nonpeptide Ag recognition by human T cells but also may provide
a novel strategic clue for immunotherapy of human
malignancy. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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2/V2+ T cells represent the
majority of circulating T cells in healthy adults
(1, 2, 3, 4, 5) and are polyclonally activated by low
molecular-mass nonpeptide Ags without prior priming (3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16). The nonpeptide Ags include microbial metabolites such as
pyrophosphomonoesters (7) and alkyl amines
(17), as well as synthetic aminobisphosphonates such as
pamidronate (18, 19, 20, 21). Unlike 
T cells, activation of
these T cells by the former nonpeptide Ags does not seem to
require the specialized APCs (22). However, it has been
shown that the intimate cellular contact was prerequisite for the
T cell clones to be activated by these Ags, leaving the
possibility open that these Ags are presented on the cells including
T cells themselves (3, 22). In contrast, we have
shown that response of the primary human
V2/V2+ T cells to pamidronate was
dependent on the monocytic adherent cells in the PBMC
(20). It was further shown that a leukemic line of
monocyte-lineage pulsed with pamidronate could also significantly
activate the primary T cells (20).
The observation has prompted us to examine an intriguing possibility
that human tumor cells of various origins might be capable of
presenting the nonpeptide Ags directly for T cells. Here, we
first indicate that human bladder cancer lines become capable of
stimulating the T cells following brief pulsing with the
nonpeptide Ags, inducing specific proliferation as well as production
of IFN-, while untreated tumor cells totally failed to do so.
Furthermore, such Ag-pulsed tumor cells were significantly more
susceptible to the direct cytolysis by the T cells than
untreated tumor cells. Survey of a number of human solid tumor lines of
distinct origins indicated that the majority of them could be
"sensitized" effectively for the T cell-mediated, but not
for nonspecific lymphokine-activated killer
(LAK)3-mediated,
cytotoxicity by pulsing with nonpeptide Ags, except for breast cancer
cell lines so far tested. The results have indicated that the ability
of presenting nonpeptide Ags to T cells was shared by many
different types, if not all, of human tumor cells. Present findings may
provide a possible link of innate immunity against microbial infection
and tumors. Based on these findings, possibility of a novel strategy of
immunotherapy for human malignancy is also discussed.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Antigenic monoethyl pyrophosphate (EtPP) was synthesized as described previously (7), and pamidronate (disodium 3-amino-1-hydroxypropylidene-1,1-bisphosphonate pentahydrate) was purchased from Novartis (Nuernberg, Germany).
Polyclonal human T cell lines and T cell clone
PBMC from healthy donors were stimulated with 200 µM
pyrophosphomonoester Ag in the presence of 10 U/ml IL-2 for 2 wk. Over
95% of such populations consisted of the
V2/V2+ T cells and were used as a
polyclonal T cell source. A V2/V2+ T
cell clone, 12G12, was reported previously (6, 7). They
were maintained in the modified Yssel’s medium as described
previously.
Tumor cell lines and Ag pulsing
Human osteosarcoma lines were kindly provided by Dr. J. Toguchida (Institute of Frontier Science, Kyoto University, Japan), and the rest of tumor cell lines were supplied from Japanese Cancer Research Resources Bank (Osaka, Japan). Tumor cells (5 x 106) were incubated with varying concentrations of pamidronate (3–100 µM) or EtPP (1000 µM) at 37°C for 1–10 h and washed five times before use.
Proliferation assay
Human polyclonal T cell line or 12G12 clone (1.5 x
105/well) was cocultured with varying numbers of
tumor cells pretreated with medium or nonpeptide Ags followed by the
mitomycin C treatment (200 µg/ml) in the 96-well round-bottom plate.
After 36 h, the cultures were pulsed with
[3H]thymidine for 12 h and counted for
radioactivity by liquid scintillation counter (7).
Cytotoxicity assay
Tumor cells (1 x 106) preincubated
with nonpeptide Ags were washed 5 times, and then labeled with 100
µCi of Na51Cr for 1 h. T cell line
or 12G12 clone was added to the labeled tumor cells (1 x
104/well) at varying effector-target ratios, and
incubated for 5 h. For cold target inhibition experiments, a fixed
number of 51Cr-labeled target cells (1 x
104/well) was mixed with varying numbers of
unlabeled tumor cells (0.25–4 x 104/well).
Specific 51Cr release was determined as described
previously (6).
Intracellular staining
Human T cell line or 12G12 clone (1 x
106/well) was cocultured with the Ag-pulsed,
mitomycin C-treated tumor cells (1 x
106/well) for 10 h and then incubated with
brefeldin A (10 µg/ml) (Sigma, St. Louis, MO) for 2 h. The cells
were harvested and stained for surface TCR-V2 and intracellular
IFN- as before (20). Briefly, the cells were first
stained with FITC-conjugated anti-TCR V2 chain, fixed with 1%
paraformaldehyde, permealized with 0.5% saponin (Wako, Richmond, VA),
and then stained with PE-conjugated anti-IFN- (BD PharMingen,
San Diego, CA). The resulting cells were analyzed on a FACScan analyzer
(BD Biosciences, San Jose, CA). Tumor cell fraction could be clearly
gated out by the forward and side-scatterings. For the analysis of
TCR expression after the coculture with tumor cells, the
harvested cells were double stained with propidium iodide (PI)
and anti-TCR V2 without fixation, and a PI-negative viable cell
fraction in the lymphocyte gate was analyzed.
Stimulation of Jurkat transfectants
V2/V2-TCR transfectants of a TCR -gene-deficient Jurkat
line were generated as described previously (20), using a
plasmid vector, pEF-BOS, kindly supplied from Dr. S. Nagata (Osaka
University Medical School, Suita, Japan). PMA-treated Jurkat
transfectants were plated out into 96-well round-bottom plates and
stimulated with varying concentrations of OKT3 mAb or with varying
numbers of tumor cells pulsed with pamidronate or EtPP. After 24
h, supernatants were harvested and assessed for IL-2 using the standard
CTLL-2 assay (20).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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2/V2+ T cells
Two independent human bladder cancer cell lines, EJ-1 and T24,
were preincubated with varying concentrations of pamidronate for
10 h. After extensive wash and mitomycin C treatment, varying
numbers of untreated or Ag-pulsed cancer cells were cocultured with the
T cells in the absence of IL-2. As shown in Fig. 1
, either polyclonal T cells or
12G12 clone showed little proliferative responses against untreated
EJ-1 or T24. In quite a contrast, both T cell populations
exhibited significant proliferative responses against the tumor cells
pretreated with pamidronate in a tumor cell number-dependent manner
(Fig. 1, A, B and D, E).
Because free pamidronate is incapable of stimulating the T cells
in the absence of accessory cells (20), the effect is most
unlikely ascribed to the passive "carry-over" of free pamidronate.
Both cancer lines pulsed with another nonpeptide Ag for
V2/V2+ T cells, EtPP, similarly stimulated
the proliferation of T cells (Fig. 1, C and
F). Although not shown, tumor cells pretreated with related
but nonantigenic pyrophosphomonoesters hardly induced the proliferation
of T cells (Y. Tanaka, Y. Kato, and N. Minato,
unpublished data). These results have suggested that the bladder cancer
cells can efficiently present the nonpeptide Ags to T cells and
induce their proliferation.
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2/V2+T cells to produce IFN- in a
TCR-dependent manner
We then examined whether the Ag-pulsed cancer cells could
functionally activate the V2/V2+ T cells.
As shown in Fig. 2, both polyclonal and
cloned T cells produced undetectable levels of IFN- by the
coculture with untreated EJ-1 or T24 cells, as judged by the
intracellular staining of the cytokine. However, when the T
cells were cocultured with the cancer lines pulsed with
pamidronate, a significant level of IFN- production was
observed in a pulsing dose-dependent manner. It was noted that the
expression of TCR was progressively down-regulated in
concordance with the increased intracellular staining for IFN- as
the pulsing doses of pamidronate increased, while the T cell
population exhibited a rather uniform expression of the TCR
before the coculture. Because FACS analysis was done in the lymphocyte
gate excluding by far larger tumor cells, the apparent increase in the
V2low fraction with significant IFN-
staining was unlikely due to the contamination of tumor cells. To
confirm this, we cocultured the T cells with untreated or
Ag-pulsed cancer cells and double stained them with PI and
anti-V2 without fixation. As shown in Fig. 3A, significant down
regulation of TCR expression in the PI-negative viable T
cell population was observed by the coculture with Ag-pulsed, but
not with untreated, cancer cells. Similar experiments were also
performed using a TCR -chain gene-defective Jurkat cells stably
transfected with V2/V2-TCR genes. Again, cancer cells pulsed
with pamidronate or EtPP, but not untreated cancer cells, specifically
induced the secretion of IL-2 (Fig. 3B). The results
indicate that the specific activation of T cells by the tumor
cells pulsed with the nonpeptide Ag is indeed dependent on the
TCR.
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2/V2+ T cells
Next, we examined the effect of Ag pulsing on the susceptibility
of the bladder cancer cells to the direct T cell-mediated
cytotoxicity. As shown in Fig. 4, both
polyclonal and cloned T cells, which were maintained in the
IL-2-containing medium, exhibited moderate cytotoxicity against
untreated EJ-1 and T24 lines. Because these tumor cells failed to
specifically activate the T cells (Figs. 1
and 2) or
TCR-transfected Jurkat cells (Fig. 3), the baseline cytotoxicity likely
reflected a so-called LAK activity by IL-2 in the culture medium. In
contrast, both T cells exhibited a markedly augmented cytotoxic
activity against both EJ-1 and T24 cancer cells pulsed with pamidronate
in a pulsing dose-dependent manner (Fig. 4, A, B
and D, E). Essentially similar results were
obtained by using the cancer cells pulsed with EtPP (Fig. 4, C and F). Although the baseline cytotoxicity
against the untreated cancer cells varied significantly depending on
the culture condition of the T cell lines and clone, the
enhancement of cytotoxicity following Ag pulsing of the tumor cells was
quite consistent and reproducible by repeated experiments. Also,
spontaneous 51Cr release from the pulsed cancer
cells was comparable with that of untreated cells, and no direct toxic
effect of pulsing with Ags was observed. In addition, pulsing with a
nonantigenic derivative was totally without effect (Y. Tanaka, Y. Kato,
and N. Minato, unpublished observation). As shown in Fig. 4G, the primary PBL stimulated with PHA, which contained
negligible T cells (<2%) but showed significant cytotoxicity
against K562 cells, exhibited no enhanced cytotoxicity against EJ-1
cells following pulsing with pamidronate. The results have indicated
that the sensitizing effect for cytotoxicity by the Ag pulsing on the
cancer cells was indeed specific for the human T cells.
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2/V2+ T cells exhibit significantly enhanced
cytotoxicity against a wide variety of human tumor cells pulsed with
nonpeptide Ags
Finally, we have extended the analysis for the sensitizing effect
of nonpeptide Ags to a wide variety of tumor cells of distinct origins.
The results are summarized in Table I.
Daudi lymphoma cells were exceptionally susceptible to the T
cell-mediated cytotoxicity as reported before (23, 24),
which was shown to be dependent on the TCR, and the pulsing with
pamidronate resulted in further enhancement of the susceptibility. In
contrast, 15 independent solid tumor cell lines of various origins were
either totally resistant or only moderately susceptible to the
cytotoxicity by polyclonal T cell line. None of them was capable
of stimulating significantly the proliferation or IFN- production of
the T cells (Y. Kato, Y. Tanaka, and N. Minato,
unpublished data; see also Fig. 5). Among
them, however, 12 tumor cell lines exhibited markedly enhanced
susceptibility to the cytotoxic activity by T cells following
pulsing with either pamidronate or EtPP. Curiously, all the three
independent breast cancer lines remained resistant to the T
cell-mediated cytotoxicity even following the Ag pulsing (Table I and
Fig. 5B). In contrast to other tumor lines, which
significantly induced the IFN- production from the T cells
following the Ag pulsing, the breast cancer lines pulsed with
pamidronate failed to stimulate the T cells to produce IFN-
either. Representative results for an osteosarcoma line (NY) and a
breast cancer line (YMB-1-E) are shown in Fig. 5A. These
results indicated that the stimulatory activity of T cells and
enhanced susceptibility to their cytotoxicity were well correlated.
Furthermore, the cold breast cancer cells (YMB-1-E) pulsed with
pamidronate hardly interfered with the cytotoxic activity of T
cells against the Ag-pulsed 51Cr-labeled EJ-1 cells (Fig. 5C), eliminating the
possibility that these tumor cells inhibited or damaged the T
cells upon interaction. Normal human PHA blast cells were little
affected by the T cells even following the pulsing with
pamidronate (Table I). These results have revealed that various, if not
all, solid tumor cells can be sensitized for the specific T
cell-mediated cytotoxicity effectively with the nonpeptide
Ags.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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2/V2+ T
cells. Thus, bladder cancer cell lines pulsed with the nonpeptide Ags
followed by extensive wash could stimulate the T cells to
proliferate and produce IFN-, while untreated cells failed to do so.
The effect was dependent on the V2/V2+
TCR, in that the Ag-pulsed, but not untreated, tumor cells could
specifically stimulate a mutant Jurkat line transfected with the
TCR. Also, the TCR expression was significantly down-regulated
following the stimulation of T cells with Ag-pulsed, but not
with untreated, cancer cells, which is indicative of the specific TCR
engagement. These results suggested strongly that the effect was indeed
the specific "presentation" of the nonpeptide Ags to T cells
by the cancer cells. As expected from this, both bladder cancer lines
pulsed with the nonpeptide Ags were found to be significantly more
susceptible to the T cell-mediated cytolytic activity than
untreated cancer cells.
So far, only few human tumor cells have been shown to be capable of
stimulating specifically the T cells, such as Daudi Burkit
lymphoma line (23, 24, 25, 26) and intestinal tumor lines
expressing MHC class I-related chain A Ag (27, 28).
In the present study, we have surveyed a wide variety of human solid
cancer or sarcoma lines of distinct origins, and none of them could
significantly stimulate the V2/V2+ T
cell lines or clone in terms of specific proliferation and IFN-
production. Although the T cell lines exhibited variable degrees
of cytotoxicity against these tumor lines, it most likely represented
LAK-like activity often associated with cytotoxic T cell lines
maintained in the IL-2-containing medium (29). Rather
surprisingly, however, the majority, if not all, of these solid tumor
cell lines pulsed with either pamidronate or EtPP exhibited markedly
enhanced susceptibility to the cytotoxic activity by T cells.
The enhancement by the nonpeptide Ag pulsing was unrelated to their
intrinsic susceptibility to the probable LAK-like activity of T
cell lines. Thus, tumor lines such as lung cancers and osteosarcomas,
which were essentially resistant to the cytotoxicity by T cell
lines, became highly susceptible following pulsing with nonpeptide Ags.
In fact, unlike untreated tumor cells, these Ag-pulsed tumor cells were
now capable of stimulating both specific proliferation and IFN-
production of the T cells.
Rather curiously, all the three independent breast cancer lines
remained totally resistant even after the Ag pulsing. Because the
copresence of Ag-pulsed breast cancer cells hardly interfered with the
cytotoxic activity of T cells against the susceptible tumor
cells, it was most unlikely that these particular cancer cells somehow
inhibited the lytic function of T cells or damaged them. Indeed,
the Ag-pulsed breast cancer lines failed to stimulate the proliferation
and IFN- production of T cells either, confirming the
correlation between the stimulatory activity of T cells and
susceptibility to their cytotoxicity. At present, several possible
explanations may be considered. First, they simply fail to present the
nonpeptide Ags due to the absence of putative Ag-anchoring molecules.
It was reported previously that the activation of T cells by the
nonpeptide Ags is independent of MHC class I, class II, CD1, TAP1/2, or
DMA/DMB (22), implicating the existence of unidentified
presentation mechanisms. In fact, our unpublished results indicate that
certain chemical modification of the tumor cells before Ag pulsing, but
not after pulsing, abrogates the Ag-presenting effect (Y. Kato, Y.
Tanaka, and N. Minato, unpublished observation). Second, they
can be pulsed with Ags, yet lack additional costimulatory molecules
possibly required for the effective activation of T cells. Most
recently, it has been reported that MICA can provide a
costimulatory signal for the V2/V2+
T cells in response to nonpeptide Ags (21). Third, these
resistant tumor cells may simultaneously deliver the negative signals
for T cells, via killer inhibitory receptors for instance
(30, 31). Besides these exceptions, however, present
results suggest strongly that the presenting capacity of nonpeptide Ags
to T cells is shared by an unexpectedly wide variety of human
solid tumor cells of distinct origins.
Modes of the nonpeptide Ag presentation by tumor cells to T
cells remain to be investigated. We have recently indicated that
specific lysine residues in germline-encoded human J1.2 segment in
the complementarity-determining region 3 of
V2/V2+ TCR are essential for the
nonpeptide Ag recognition by the T
cells,4 which
is compatible with the most recent structural implication based on the
crystallized V2/V2+ TCR
(32). We speculate that yet unidentified anchoring
molecules on various tumor cells are capable of presenting the low
molecular mass-nonpeptide Ags to the positively charged Ag-binding
pocket in a proper orientation. Sets of tumor lines with and without
Ag-presenting capacity may provide useful means for the molecular
identification of such anchoring molecules for the nonpeptide
Ags.
We reported previously that activation of the primary T cells by
pamidronate was critically dependent on normal macrophages in PBMC for
the effective Ag presentation (20). However, our
unpublished results indicate that the macrophages can hardly stimulate
the preactivated T cells such as T cell lines and clones
used in the present study (Y. Tanaka and N. Minato, unpublished
observation). These results coincide with the reported clinical
observations in human that, while the first administration of
pamidronate induces adverse effects such as fever attributable to the
massive release of IFN-, subsequent repetitive administration is
well tolerated with little adverse effects (33, 34, 35, 36, 37, 38, 39). In
contrast, our previous (20) and present results have
indicated that certain tumor cells are capable of presenting the
nonpeptide Ags to both the primary and preactivated T cells
quite efficiently. Thus, it is implied that the mode of Ag presentation
by tumor cells might differ significantly from that by normal
macrophages either quantitatively or qualitatively. Although
presentation of nonpeptide Ags by normal cells such as macrophages may
be effective only upon the initial exposure in vivo and thus transient,
that by tumor cells may well persist as long as the Ags are
available.
It has been reported that microbial infection in patients bearing
malignancy may modify the course of tumor progression
(40). Also, it is reported that bacillus
Calmette-Guérin vaccine application can exhibit significantly
beneficial effect in controlling the malignancy, in particular the
bladder cancers (41, 42). Because many microbes are
indicated to produce and secrete nonpeptide Ags for human T
cells such as alkyl pyrophosphates and alkyl amines
(43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55), it is tempting to speculate that these microbial
nonpeptide Ags may contribute to the restriction of growth of
incidental tumor cells via stimulation of T cells to proliferate
and produce IFN- as well as sensitization of the tumor cells for the
T cell-mediated cytotoxicity. Our recent report suggested that
T cells might provide innate immunity in patients with renal
cell carcinomas, implicating a possible link between tumor immunity and
urinary infections (56). Although more careful and
extensive analysis is certainly needed for the possible sensitizing
effect of nonpeptide Ags on normal cells in various tissues toward
T cell-mediated cytotoxicity, our present results may
provide a strategic clue to develop novel approaches for immunotherapy
of human malignancy.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Nagahiro Minato, Department of Immunology and Cell Biology, Graduate School of Medicine, Kyoto University, Yoshidakonoe-Cho, Sakyo-Ku, Kyoto, 606-8501, Japan. E-mail address: minato{at}imm med.kyoto-u.ac.jp
3 Abbreviations used in this paper: LAK, lymphokine-activated killer; EtPP, monoethyl pyrophosphate; PI, propidium iodide.
4 F. Miyagawa, Y. Tanaka, S. Yamashita, B. Mikami, K. Danno, M. Uehara and N. Minato. Essential contribution of germline-encoded lysine residues in J1.2 segment to the recognition of nonpeptide antigens by human T cells. Submitted for publication.
Received for publication August 15, 2001. Accepted for publication August 31, 2001.
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L. Conti, R. |
, medium alone; •, 10 µM; 
, 30 µM; or 
,
100 µM in A, B, D, and
E) or EtPP (
) for 24 h. IL-2 activity in the culture supernatants were
assessed by the standard CTLL-2 proliferation assay (
