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1.2 Segment to the Recognition of Nonpeptide Antigens by Human 
T Cells1
*
Department of Immunology and Cell Biology, Graduate School of Medicine, and
Graduate School of Biostudies, Kyoto University, Kyoto, Japan;
Department of Dermatology, Shiga University of Medical Science, Ohtsu, Shiga, Japan; and
Department of New Food Design, Graduate School of Agriculture, Kyoto University, Gokasho, Uji, Kyoto, Japan
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Abstract |
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T cells display unique repertoires of Ag specificities
largely imposed by selective usages of distinct V and V genes.
Among them, V2/V2+ T cells predominate in the
circulation of healthy adults and respond to various microbial small
molecular mass nonpeptide Ags. The present results indicate that the
primary V2/V2+ T cells stimulated with the distinct
groups of nonpeptide Ags, including monoethyl pyrophosphate, isobutyl
amine, and aminobisphosphonate, invariably exhibit J1.2 in the
V2+ TCR- chains. Gene transfer studies revealed that
most of the randomly cloned V2/J1.2+ TCR- genes
bearing diverse V/J junctional sequences could confer the
responsiveness to all these nonpeptide Ags, while none of the
V2/J1.1+ or V2/J1.3+ TCR- genes
could do so. Furthermore, mutation of the lysine residues encoded by
the J1.2 gene, which are unique in human J1.2 and absent in other
human or mouse J segments, completely abrogated the responsiveness
to all the nonpeptide Ags without affecting the response to
anti-CD3 mAb. These results strongly suggested that the positively
charged lysine residues in the TCR- chain CDR3 region encoded by the
germline J1.2 gene play a key role in the recognition of diverse
small molecular mass nonpeptide Ags. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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T cells represent a subset of the T cell population with
distinct characteristics from 
T cells in terms of development,
phenotypes, tissue distribution, and mode of Ag recognition
(1, 2, 3, 4). Several lines of evidence have indicated that
T cells display a unique repertoire of Ag specificities
(1). Reported Ags for T cells are quite diverse,
including low molecular mass nonpeptide products derived from a variety
of microbes (5, 6), nonclassical MHC class I (T10, T22)
molecules (7), and HSV glycoprotein (8, 9).
Such diverse Ag specificities appear to be imposed at least
partly by the usage of selective V genes for TCR- and - chains. A
number of studies have indicated that V2/V2 TCR-bearing
(V2/V2+) T cells are selectively increased
in the circulation during a variety of infections in human
(10, 11, 12, 13, 14, 15, 16, 17, 18, 19). Preferential usage of J1.2 gene has been also
noted in such a T cell population (5, 20, 21). The
activation and expansion of V2/V2+ T cells
during these infections may be mediated by the microbial low molecular
mass nonpeptide products such as pyrophosphomonoesters and alkyl amines
(22, 23, 24, 25). More recently, synthetic therapeutic compounds,
aminobisphosphonates, were reported also to stimulate the
V2/V2+ T cell subset both in vitro and in
vivo (26, 27). Evidence has indicated that the response of
the T cells to all these diverse nonpeptide products is
dependent on the V2/V2+ TCR-
(24, 28), although their direct interaction with
TCR- remains to be proved. The T cell subset produces
abundant IFN- and is believed to play a role in the control of
infection (29, 30).
On the other hand, MHC-related MICA Ag exclusively activates
V1/V1+ T cells in humans, which are mostly
located in the intestinal tissue (31). Specific reactivity
of T cells to CD1c expressed on normal APCs is also confined to
the V1+ T cells (32). MICA and
CD1 are induced to express on intestinal epithelial cells by various
stresses or transformation (33) and on various APC
(34), respectively. Thus, it is speculated that the
V1+ T cells are involved in the control of
inflammation by noninfectious stress, epithelial integrity, tumor
surveillance, as well as the regulation of adaptive immune responses
(35).
These results imply the significant contribution of diverse
germline sequences of TCR- for their distinct specificities, akin
to the diversity in the receptors of the innate immune system
(36). In this aspect, it is noteworthy that intra- and
interspecies divergences in the V gene sequences are unusually high
compared with those in V and V genes (37), and that
some of the unique repertoire of Ag specificities observed in human
T cells is not conserved in mouse. In the present study we
attempted to analyze the possible contribution of the CDR3 region of
the V2+ TCR- chains by the TCR gene
transfer system. We provide evidence that specific lysine residues in
the CDR3 region of TCR- chains uniquely encoded by the germline
J1.2 gene play a crucial role in the response of
V2/V2+ T cells to all the different groups
of nonpeptide Ags.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Monoethyl pyrophosphate (EtPP)3 was prepared as described previously and converted into its sodium salt (23, 24). Isobutyl amine (IBA) and pamidronate were obtained from Sigma-Aldrich (Tokyo, Japan) and Novartis (Nuremberg, Germany), respectively.
Cells and cultures
J.RT3-T3.5, a TCR- chain gene-defective mutant line of human
Jurkat cells, was maintained in RPMI 1640 medium supplemented with 10%
FCS, penicillin, streptomycin, and 5 x
10-5 M 2-ME. A V2/V2 T cell clone, 12G12,
established from a patient with lepromatous leprosy was repetitively
stimulated with EtPP and IL-2 in modified Yssel’s medium supplemented
with human serum albumin. EJ-1, a human bladder tumor line, was
cultured in RPMI 1640 (Sigma-Aldrich) supplemented with 10% FCS. PBMCs
were separated by Ficoll-Hypaque gradient centrifugation and cultured
at 2.5 x 106 cells/well in a 24-well plate
for 14 days in the modified Yssel’s medium supplemented with 10 U/ml
IL-2 in the presence or the absence of 0.2 mM EtPP, 1 mM IBA, or 10
µM pamidronate. The proportion of V2/V2+
T cells was analyzed by two-color staining with FITC-conjugated
anti-TCR V2 and PE-conjugated anti-CD3 using FACScan.
V/J junctional sequence analysis
cDNAs were synthesized from 5 µg total RNA extracted from the
primary T cell population in the cultures stimulated with the
Ags by using a Superscript II preamplification system (Invitrogen,
Groningen, The Netherlands) and amplified with PCR to obtain
full-length TCR- chain cDNAs using primers within the
5'-untranslated regions of the V2 gene
(ggg-ctc-gag-gac-acc-gct-tta-caa-cga) and within the 3'-untranslated
regions of the C gene (ggg-tct-aga-gtg-agg-ttc-tct-gtg-t). The PCR
products were subcloned into pBKS plasmid. For sequencing of V/J
junction, the plasmids (1 µg) were mixed with a dRhodamine Terminator
RR Mix (ABI PRISM, PE Applied Biosystems, Foster, CA) and a primer for
the V2 coding region (5'-act-ctc-acc-att-cac-aat-gta-gag-aaa-cag-3')
and were sequenced with 377 DNA Sequencer (ABI PRISM, PE Applied
Biosystems).
Site-directed mutagenesis of J1.2
TCR--chain cDNAs with a single residue mutation in the
J1.2 (M1 for K1 to E, M2 for
K2 to E, M3 for K3 to E)
were prepared using the Sculptor in vitro mutagenesis system (RPN 1526,
Amersham, Tokyo, Japan) according to the manufacturer’s protocol.
Oligonucleotides used for the mutagenesis were
gga-gtt-ggg-cga-aaa-aat-caa-gg, gag-ttg-ggc-aaa-gaa-atc-aag-g, and
ggg-caa-aaa-aat-cga-ggt-att-tgg for M1, M2, and M3, respectively.
TCR gene transfection
Full-length cDNAs for TCR- chain genes obtained as described
above and a TCR- chain gene isolated from the 12G12 clone were
subcloned into a pEF-BOS expression vector, provided by Shigekazu
Nagata (Osaka University, Suita, Osaka, Japan) and linearized as
described previously (29). J.RT3-T3.5 cells (1.5 x
107) were transfected with 50 µg each of the
digested pEF-BOS -chain and pEF-BOS -chain together with 0.7 µg
of the digested pST-NeoB by electroporation at 360 V and 500 µF using
a Bio-Rad Gene-Pulser (Hercules, CA). After 48 h the cells were
plated out into 20 96-well round-bottom plates and cultured in the
presence of 1 mg/ml geneticin (Invitrogen, Groningen, The Netherlands).
The resulting transfectants obtained after 3 wk were analyzed for the
surface expression of TCR-/CD3 by FACScan.
Ag pulsing
EJ-1 cells (5 x 106 cells/ml) were treated with mitomycin C (100 µg/ml) for 30 min and then incubated with various concentrations of pamidronate at 37°C for 90 min, followed by an extensive wash with medium before coculture with Jurkat transfectants.
Stimulation of Jurkat cell transfectants
The selected CD3+ Jurkat transfectants
expressing TCR- were preincubated with 10 ng/ml PMA at room
temperature for 30 min. As previously reported (38), PMA
treatment was essential for TCR-mediated activation in this system.
After the extensive wash with modified Yssel’s medium, the cells were
plated out into 96-well round-bottom plates at 2 x
105/200 µl in the presence of a serial dilution
of stimulants (anti-CD3 mAb, EtPP, or IBA) or EJ-1 cells pulsed
with pamidronate as described above. After 24 h supernatants were
harvested and frozen at -80°C until IL-2 assay. For determination of
IL-2, an IL-2-dependent T cell line, CTLL-2, was incubated at 3 x
103/well in 96-well round-bottom plates with
culture supernatant at a dilution of 1/5. Then, the cells were pulsed
with [3H]thymidine (0.5 µCi/ml) for 27 h
and harvested at 31 h, followed by measurement of radioactivity on
a liquid scintillation counter.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1.2 gene in the
V2/V2+ T cell population stimulated with distinct
groups of nonpeptide Ags
PBMC from healthy adults were cultured for 14 days with
200 µM EtPP, 1 mM IBA, or 10 µM pamidronate in the presence of IL-2
(10 U/ml). The stimulation resulted in the massive and selective
expansion of V2/V2+ T cells, with the mean
proportion in total CD3+ cells being 93.0 ±
2.8% for EtPP, 96.6 ± 3.1% for IBA, and 85.3% ± 6.4% for
pamidronate in five independent donors. To examine the possible
involvement of the CDR3 region, we first examined the J gene usage
of TCR--chains of such expanded V2/V2+ T
cell populations with RT-PCR. As summarized in Table I
, the usage of J1.2 gene predominated
in all V2/V2+ T cell populations stimulated
with the three different groups of nonpeptide Ags. Essentially
similar results were obtained in four other donors. Although not shown,
the V/J junctional sequences were quite diverse in all the
populations.
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1.2 segment of TCR- chain in the activation
of V2/V2+ T cells by soluble EtPP or IBA
Since J1.2 gene usage also predominates in the freshly isolated
V2/V2+ T cells of healthy adults (data not
shown), the almost exclusive J1.2 usage after stimulation with
nonpeptide Ags could be a mere reflection of this. To examine the
possibility, we isolated 11 independent V2+
TCR--chain cDNAs from the T cell population stimulated as
described above, and transformed a TCR-deficient
CD3- Jurkat cell line, J.RT-T3.5, together with
a fixed TCR- chain cDNA. Among them, one exhibited J1.1, seven
J1.2, and three J1.3, all bearing distinct V/J junctional
sequences (see Table II). The TCR-
chain cDNA was derived from a T cell clone, 12G12, capable of
responding to the Ags. After the drug selection, clones expressing high
levels of CD3 and TCR- on the surface as judged by FACS analysis
were isolated; the mean fluorescence intensities of CD3 are indicated
in Table II. All CD3+ transfectant clones
variably responded to anti-CD3 mAb stimulation, most likely
reflecting the inevitable clonal variance for IL-2 production, and the
clones with the highest response to anti-CD3 mAb were selected for
each transfection. Because EtPP and IBA are capable of activating the
cloned T cells in the absence of other particular accessory
cells (24, 25), each clone was stimulated directly with
varying concentrations of EtPP or IBA. The maximal responses of all
clones and the representative dose-response curves of those bearing
different J are shown in Table II and Fig. 1, respectively. Among seven clones
transfected with the distinct V2/J1.2+
TCR- chain genes, six clones exhibited significant levels of IL-2
production in response to both EtPP and IBA; the degrees of response
tended to parallel those to anti-CD3 mAb. Exceptionally, one clone,
KG81D2-27, differentially responded to these Ags. It was noted that
this V2/J1.2+ gene had as many as five N
region-coded residues, while all six other responsive genes contained
less than two residues in the N region (Table II). On the other hand,
none of the four clones transfected with
V2/J1.1+ or
V2/J1.3+ TCR- chain genes showed
detectable IL-2 production at any concentration in response to either
Ag, while they significantly responded to anti-CD3.
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1.2 segment is also essential for the response of
V2/V2+ T cells to pamidronate presented on the
accessory cells
Unlike EtPP and IBA, activation of
V2/V2+ T cells by pamidronate is dependent
on the presence of other APC (29). Because
V2/V2+ T cell clones can be efficiently
activated by certain cell lines pulsed with pamidronate
(29), we also examined the requirement of J1.2 in the
response to pamidronate. The Jurkat transfectants with different J1
segments described above were cocultured with EJ-1 cells preincubated
with varying concentrations of pamidronate followed by extensive
washing. All six V2J1.2+ transfectants that
responded to EtPP and IBA also produced IL-2 in response to EJ-1 cells
pulsed with pamidronate in a pulse dose-dependent manner (Table II
and
Fig. 1). The response was 4- to 50-fold greater than that to untreated
EJ-1 cells. In contrast, neither clones with
V2/J1.1+ nor
V2/J1.3+ TCR- chain genes exhibited
increased IL-2 production in response to pamidronate-pulsed EJ-1
compared with untreated EJ-1 cells (Table II). We then comparatively
analyzed the response of an exceptional
V2J1.2+ clone, KG81D2-27, to soluble EtPP
and pamidronate pulsed on the cells in the same conditions. Although
the clone again exhibited no detectable response to free EtPP at any
concentration (Fig. 2A), it
significantly responded to pamidronate-pulsed EJ-1 cells in a pulse
dose-dependent manner, albeit much less compared with a representative
V2/J1.2+ clone (Fig. 2B). This
made a contrast with a V2/J1.3+ clone,
which showed no detectable response to the pamidronate-pulsed EJ-1
cells (Fig. 2B). These results strongly suggested the
essential requirement for J1.2 in the response to all distinct
groups of nonpeptide Ags.
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1.2 gene abrogates the specific responsiveness of
V2/V2+ T cells to all groups of nonpeptide Ags
We finally intended to verify the structural basis of J1.2 for
the activation of V2/V2+ T cells by the
nonpeptide Ags. While the germline-encoded amino acid sequences of J
genes are fairly conserved through human to mouse, several N-terminal
residues are diverse (Fig. 3A). It is particularly noted
that the human J1.2 segment has a stretch of positively charged
lysine residues, KKIK, in this region. The first two lysine residues
(tentatively termed K1 and
K2) are present only in human J1.2, while the
last K (K3) is perfectly conserved in all J
genes of both species. We therefore focused on these lysine residues
and replaced each lysine residue of a
V2/J1.2+ TCR- chain cDNA clone (MAGD2-3)
with an oppositely charged glutamate residue to give MAGD2-3-M1, -M2,
and -M3, respectively (Fig. 3B). During the preparation of
this manuscript, the three-dimensional structural model of the human
TCR- has become available, and it is expected that the
K1 and K2 residues are
exposed to the surface (Fig. 3C). These mutant TCR- chain
cDNAs were again cotransfected along with a 12G12 TCR- chain cDNA
into J.RT3-T3.5 cells. After the geneticin selection,
CD3+ clones were detected at a frequency of 6.8%
for M1 and 6.7% for M2 among approximately 150 clones of each, which
was comparable to our regular transfection efficiency. In contrast, no
single CD3+ clone was obtained for M3 by
screening >1200 clones, suggesting that the conserved
K3 may be critical for the cell surface
expression of TCR- in association with CD3.
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, both M1 and M2 clones secreted
comparable levels of IL-2 in response to anti-CD3 mAb to the
wild-type transfectant clone, MAGD2-3. In contrast to the MAGD2-3
clone, however, the M1 or M2 clone produced no detectable IL-2 in
response to free EtPP or IBA at any concentration examined. We also
compared the response to pamidronate. All clones were hardly activated
with pamidronate in its free form, as expected. MAGD2-3, however,
produced significant IL-2 in response to pamidronate-pulsed EJ-1 cells
in a pulse dose-dependent manner. In contrast, neither the M1 nor M2
clone responded to the pamidronate-pulsed EJ-1 cells. These results
indicated that the unique lysine residues in the CDR3 region encoded by
the germline J1.2 gene play an essential role in the activation of
human V2/V2+ T cells by all three groups of
small nonpeptide Ags.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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2/V2+
T cells responsive to mycobacterial extracts and certain tumor
cells (21) as well as different types of defined low
molecular mass nonpeptide Ags (present results) use J1.2 in the
TCR- chain genes. In the present study we have examined the role of
J1.2 in the specific response of V2/V2+
T cells to representative nonpeptide Ags of distinct groups,
including EtPP, IBA, and pamidronate, using the gene transfer system
(29). First, it was found that almost all randomly
selected V2/J1.2+ TCR- chain genes could
successfully transfer the responsiveness to all nonpeptide Ags, while
none of them bearing other J segments, such as J1.1 or J1.3,
failed to do so. There was an exceptional
V2/J1.2+ TCR- chain gene that failed to
confer the responsiveness to soluble EtPP. This particular clone,
KG81D2-27, however, exhibited a rather weak, yet significant, response,
when stimulated with pamidronate pulsed on APC.
V2/J1.1+ or
V2/J1.3+ clones, on the other hand,
remained totally unresponsive even to this form of Ag. We therefore
consider that the KG81D2-27 clone still retains Ag responsiveness,
although the efficiency is reduced markedly (see below). It is
suggested strongly that J1.2 in the V2+
TCR--chains is indispensable for the response to the nonpeptide
Ags.
We then addressed the structural basis for requirement of J1.2 by
using site-directed mutagenesis of a
V2/J1.2+ gene. We focused on the three
lysine residues in the N-terminal region of J1.2, because the most
N-terminal two lysines (K1 and
K2) are unique in J1.2 and not shared with
other J, while the third lysine (K3) is
conserved in all J. Since the antigenically critical moieties of all
nonpeptide Ags have electric charges (23, 24, 25, 26), we presumed
that the positive charge of the lysine residues might be important and
therefore mutated each of them into oppositely charged glutamate. It
has been suggested strongly that K3 is essential
for the proper pairing of TCR- with TCR- chains, because no
single CD3+ clone could be generated by
cotransfection of the K3 mutant TCR- and
TCR- genes. The three-dimensional structure predicts that
K3 is buried and not exposed on the molecular
surface of TCR- (Fig. 3C). In contrast, both
K1 and K2 mutants resulted
in the establishment of CD3+ clones with
comparable frequency to that of the wild-type TCR- gene, indicating
that the overall structure of TCR- containing the mutants was
largely maintained, at least enough to be expressed on the cell surface
in association with CD3. Both mutant clones indeed responded to
anti-CD3 mAb stimulation comparably to the wild-type clone.
However, they completely failed to respond to EtPP and IBA. Neither
mutant clone responded to pamidronate presented on EJ-1 cells,
indicating the complete abrogation of responsiveness. Thus, it has been
suggested strongly that the germline-encoded lysine residues of J1.2
in the CDR3 region are critical for the response of T cells
to all defined nonpeptide Ags. Also, the results may well explain why
such a responsiveness to nonpeptide Ags is not observed in murine
T cells.
Very recently, the x-ray crystallographic structure of human TCR-
was reported (39). It revealed the presence of a putative
Ag-binding pocket on the exposed surface of TCR-. The unique
pocket structure contains at least three positively charged residues at
the bottom, arginine (CDR2), lysine (CDR3), and arginine
(CDR2), among which the lysine (CDR3) of JP (J1.2)
corresponding to K2 in this study is speculated
to be a key residue of the putative Ag binding site (39).
Our present functional analysis perfectly coincides with this
structural prediction. On the other hand, analysis of fine Ag
specificity has revealed that even trivial changes in the hydrocarbon
chains of pyrophosphomonoester Ags result in a marked reduction of
antigenicity (23, 24), implicating the additional
requirement of appropriate hydrophobic moiety in the vicinity of the
charged binding site. It is proposed that conserved hydrophobic
residues of V2 adjoining the lysine residues of J1.2 may
contribute to the interaction with hydrophobic parts of the nonpeptide
Ags (39). In either case, these results collectively
suggest that the appropriate three-dimensional structure of the pocket
is required for the highly specific recognition of nonpeptide Ags, in
which the lysine residue(s) provided by J1.2 segment plays a key
role. An exceptional V2/J1.2+ TCR- gene
(KG81D2-27), described above, contained an unusually long N insertion,
encoding as many as five amino acid residues, while the responsive
V2/J1.2+ TCR- genes encoded less than
two residues. Such an extended CDR3 region might disturb the proper
pocket structure despite the presence of J1.2 lysine residues,
resulting in a marked, if not complete, reduction of Ag responsiveness.
A significant contribution of the V/J junctional region to the
response to pyrophosphomonoester Ag was reported previously
(40). On the other hand, in a few rare T cell
clones without J1.2, which were reported to react weakly with
nonpeptide Ags, positively charged resides in a similar position at the
CDR3 loop may partially replace the functional role of the lysine
residue normally provided by J1.2 (39).
It remains to be formally proved whether the nonpeptide Ags indeed bind
to the putative Ag-binding pocket of TCR- and, if so, how. In
this respect it is particularly noted that among the nonpeptide Ags
pamidronate strictly requires the presentation by certain types of
cells for effective stimulation of T cells (29, 41), although the requirement of Ag presentation remains
controversial for other Ags, such as EtPP and IBA (5, 6, 10, 42). As discussed above, pamidronate pulsed on the presenting
cells could significantly activate a rare
V2/J1.2+ T cell clone that totally failed
to respond to soluble Ags. Thus, it may be speculated that the APC help
to stabilize the Ag in a proper orientation for the putative Ag-binding
pocket of T cells. It also remains to be seen how distinct
nonpeptide Ags similarly interact with the Ag-binding pocket, including
EtPP, bearing negatively charged pyrophosphate, and IBA and
pamidronate, with positively charged amines as antigenically critical
moieties (22, 42, 43, 44, 45, 46, 47, 48).
While V2/V2+ T cells, the major
circulating T cell population in healthy adults, predominantly
express J1.2, those in the cord blood use diverse J genes (our
unpublished observation). Thus, it is suggested that the dominance of
V2/J1.2/V2+ T cells in adults may
reflect the epigenetic selection during human development, consistent
with previous reports on identical twins (49). Since the
antigenic nonpeptide metabolites derived from a wide variety of
microbes may be rather ubiquitous, it is speculated that persistent
exposure to the environmental micro-organisms provides the major
selection force for this particular set of T cells in humans.
Reported memory phenotypes of the majority of T cells in adults
support this possibility (50). The present results
reinforce that V2/V2+ T cells in humans
play important roles in infection as part of innate immunity through a
unique mode of pattern recognition of diverse bacterial nonpeptide Ags,
largely via germline-encoded TCR- (51, 52, 53, 54).
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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: EtPP, monoethyl pyrophosphate; IBA, isobutyl amine.
Received for publication September 4, 2001. Accepted for publication October 16, 2001.
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) or soluble EtPP (•)
for 24 h, and IL-2 in culture supernatants was assessed. Mean
counts per minute and SEs of triplicate culture are indicated.
B, Transfectant clones
G161D2-27/V
),
KG81D2-27/V
), and
KG2D2-19/V
) were
cocultured with EJ-1 cells pulsed with varying concentrations of
pamidronate for 24 h, and IL-2 in culture supernatants was
assessed. Mean counts per minute and SEs of triplicate culture are
indicated. Refer to Table II
