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Requirement of Species-Specific Interactions for the Activation of Human T Cells by Pamidronate¹

Yu Kato^*, Yoshimasa Tanaka^*,, Hidenori Tanaka, Seiji Yamashita^* and Nagahiro Minato^2,*,

^* Department of Immunology and Cell Biology, Graduate Schools of Biostudies and Medicine, Kyoto University, Kyoto, Japan; and PRESTO, JST, Kyoto, Japan

	Abstract

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Human T cells bearing V2V2-TCR recognize various kinds of small nonpeptide Ags, and activation of them by a nitrogen-containing bisphosphonate Ag, pamidronate, requires Ag presentation by cells other than T cells, including many human tumor cells. Present results demonstrated that tumor cell lines of nonhuman origins pulsed with pamidronate failed to activate human T cells without exception, whereas most if not all human tumor cell lines could do so. T cells formed stable conjugates with pamidronate-pulsed human tumor cells and both conjugate formation and T cell activation were inhibited significantly by anti-LFA-1 mAb, suggesting the requirement of LFA-1-mediated interaction with APC for efficient T cell activation. Consistently, ICAM-1^low tumor cell lines pulsed with pamidronate induced no or only weak activation of T cells, whereas similarly treated ICAM-1^high cell lines could activate them. One of the two ICAM-1^low tumor cell lines pulsed with pamidronate induced strong T cell activation after ICAM-1 gene transfer. However, another ICAM-1^low human cell line as well as murine tumor cell lines pulsed with pamidronate remained totally defective in T cell activation even after expression of human ICAM-1. These results suggested that activation of human T cells by nonpeptide Ags required species-specific interactions in addition to LFA-1/ICAM-1-mediated cell adhesion with APC.

	Introduction

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Human T cells bearing V2V2- TCR, a predominant T cell subset found in adult peripheral blood, specifically recognize various kinds of nonpeptide Ags (reviewed in Ref. 1), such as bacterial pyrophosphomonoesters (2, 3, 4, 5) and alkyl amines (6) as well as synthetic nitrogen-containing bisphosphonates (7, 8, 9) in the V2V2- TCR-dependent manner (2, 3, 4, 5, 6, 7, 8, 9, 10, 11). However, it remains unknown how the TCR recognizes such nonpeptide Ags of small molecular masses. We previously reported that the recognition was dependent on the lysine residues encoded by a germline J1.2 gene segment proximal to the junctional region (11) located in a putative Ag-binding pocket (12). These lysine residues are not conserved in other human nor murine J segments, which may in part explain why recognition of these nonpeptide Ags is a unique feature of human V2J1.2V2- T cells. Among nonpeptide Ags, nitrogen-containing bisphosphonates such as pamidronate were rather unique, in that activation of the primary T cells required the presence of monocytes (9). Furthermore, many if not all human tumor cell lines prepulsed with pamidronate could efficiently activate human T cells, whereas no TCR-dependent recognition was observed in mock-treated tumor cells (13). These results strongly suggested that pamidronate had to be "presented" by selected cells other than T cells per se for effective T cell activation.

In the present study, we show that the optimal activation of T cells by pamidronate-pulsed human tumor cells was dependent on the stable cell adhesion mediated by LFA-1 expressed on T cells and ICAM-1 on the Ag-pulsed tumor cells. Although human tumor cell lines with high ICAM-1 expression (ICAM-1^high) could efficiently present pamidronate to T cells, a minor population with little or no expression of ICAMs (ICAM-1^low) as well as any of the tumor cell lines of nonhuman origins pulsed with pamidronate failed to activate human T cells. Human ICAM-1 expression by cDNA transfer could confer the strong T cell-activating capacity in one ICAM-1^low human tumor cell line. However, no such induction was observed in another ICAM-1^low human tumor as well as mouse tumor cell lines, suggesting the requirement of additional species-specific interaction(s) with Ag-presenting tumor cells for the effective activation of T cells by a nonpeptide Ag, pamidronate. These results argue for the presence of a specific mechanism for nonpeptide Ag presentation to human T cells, complementing that for T cell activation by peptide Ags.

	Materials and Methods

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Nonpeptide Ags

Monoethyl pyrophosphate was synthesized as described previously (4) and pamidronate was purchased from Novartis Pharma (Nuernberg, Germany).

Human T cells

PBMC were separated from healthy volunteers’ blood using Ficoll-Paque (Pharmacia Biotech, Uppsala, Sweden) and stimulated with 0.2 mM monoethyl pyrophosphate in Yssel’s medium supplemented with 2.5% human serum albumin for 2 days. The cells were further cultured in Yssel’s medium containing 10% human AB sera and IL-2 (100 U/ml) for 14 days. The proportions of V2V2-bearing T cells in such populations were consistently 95% or more in CD3-positive cells and were used as polyclonal T cell lines in the present study.

Tumor cell lines and pulsing with nonpeptide Ag

Tumor cell lines of human and nonhuman origins were supplied from Human Science Research Resource Bank (Osaka, Japan) and cultured according to the original instructions. To pulse the tumor cells with pamidronate, 1.0 x 10⁶ tumor cells were incubated with 0.1 mM pamidronate for 2 h at 37°C and washed extensively with RPMI 1640 containing 10% FCS before use.

Flow cytometry and mAbs

Single- and two-color flow cytometric analyses were conducted using FACScan (BD Biosciences, Mountain View, CA) as described previously (13). mAbs used in the present study were anti-TCR 2 (Immunotech, Marseille, France), anti-IFN- (BD PharMingen, San Diego, CA), anti-ICAM-1, -2, and -3 (BD PharMingen), anti-LFA-1 (TS1/22), and anti-LFA-1 specific for an activated form (NKI-L16), kindly provided by Dr. T. Kinashi (Kyoto University, Kyoto, Japan).

Proliferation assay

Human T cells were cocultured at 1.0 x 10⁵/well with varying numbers (1.2 x 10³–2.0 x 10⁵) of mitomycin C (100 µg/ml)-treated tumor cells at 37°C for 36 h and pulsed with [³H]thymidine (2 µCi) for 12 h, and radioactivity incorporated in DNA was counted by a MicroBeta scintillation counter (PerkinElmer Life Sciences, Norwalk, CT).

Cytotoxicity assay

Tumor cells (1.0 x 10⁶) pretreated with 0.1 mM pamidronate were labeled with 100 µCi of [⁵¹Cr]sodium chromate for 1 h at 37°C. Varying numbers of human T cells (0.625 x 10⁴–4.0 x 10⁵) were cocultured with 1.0 x 10⁴ tumor cells for 5 h, and ⁵¹Cr release was counted by a gamma counter (PerkinElmer Life Sciences).

Intracellular IFN- staining

Human T cells (5.0 x 10⁵/well) were cocultured with pamidronate-pulsed tumor cells (5.0 x 10⁵/well) at 37°C. After 2 h, brefeldin A (10 µg/ml) (Sigma-Aldrich, St. Louis, MO) was added in the culture and the cells were incubated for another 2 h. The cells were then washed and stained with FITC-conjugated anti-TCR-V2 mAb on ice for 20 min. The cells were washed twice, fixed with 1% paraformaldehyde, permeabilized with 0.5% saponin, and stained with PE-conjugated anti-IFN- mAb for 20 min. After washing three times, the cells were analyzed using FACScan (BD Biosciences).

Conjugation assay

Tumor cells were stained with PKH26 (Molecular Probes, Eugene, OR) at room temperature for 5 min and human T cells were stained with CFSE (Molecular Probes) at 37°C for 15 min. After washing, the labeled T cells and tumor cells were incubated for varying periods and were two-color analyzed after gentle vortexing using FACScan.

Human ICAM-1 cDNA transfection

A full-length human (h)³ ICAM-1 cDNA was kindly provided by Dr. O. Takashi (Daiichi Pharmaceutical, Tokyo, Japan). Tumor cell lines were transfected with hICAM-1 cDNA constructed in a pEF-BOS expression vector, kindly provided by Dr. S. Nagata (Osaka University, Suita, Osaka, Japan), by electroporation using ECM830 (BTX). The cells were cultured in the medium containing 1 mg/ml G418 (Nacalaitescque, Osaka, Japan) and screened for the expression using anti-ICAM-1 mAb to establish stable clones highly expressing hICAM-1.

	Results

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Pamidronate-pulsed tumor cells derived from nonhuman species fail to activate human T cells

Most human tumor cell lines from various tissues pulsed with pamidronate for 2 h activated human T cells in terms of IFN- production, proliferation, and specific cytotoxicity to varying degrees, while a minor population failed to do so, with representative data being shown in Table I. Without Ag pulsing, none of them could induce IFN- production or specific proliferation. In contrast, tumor cell lines from nonhuman species similarly pulsed with pamidronate at any doses totally failed to activate human T cells (Table I). As summarized in Table II, none of the 33 tumor cell lines pulsed with pamidronate from 12 different species other than human could activate human T cells, whereas a significant level of IFN- was observed in human T cells in response to 21of 26 human tumor cell lines pulsed with pamidronate. An effective Ag-pulsing effect was detected by the incubation with pamidronate for as little as 2 h. After the pulsing with 0.1 mM pamidronate for 2 h, no significant toxic effect was observed as judged by propidium iodide staining in both human and nonhuman tumor cell lines (data not shown), excluding a possibility that the different "pulsing effect" reflected differential sensitivity of each cell line to the toxic metabolic effects by pamidronate. The results strongly suggested that effective presentation of pamidronate to human T cells by tumor cells required species-specific cellular interactions.

View this table: [in this window] [in a new window]   Table I. Stimulation of human T cells by pamidronate-pulsed tumor cell lines derived from human and other animal speciesa

View this table: [in this window] [in a new window]   Table II. Summary of the human V2V2 T cell activation by pamidronate-pulsed tumor cell lines originated from human and other animal speciesa

Requirement of LFA-1/ICAM-1-mediated adhesive interaction for effective activation of human T cells by pamidronate-pulsed human tumor cells

We previously reported that pamidronate specifically induced the clustering between human T cells and accessory monocytes, suggesting the requirement of direct cellular adhesion for effective T cell activation (9). As indicated in Fig. 1A, both primary and activated human T cells highly expressed LFA-1 in an active form. On the other hand, human tumor cell lines, which could efficiently present pamidronate to T cells, expressed ICAM-1, with representative examples being indicated in Fig. 1B. In contrast, a minor population of human tumor cell lines with no or only weak capacity to activate T cells exhibited only marginal LFA-1 ligand expression including ICAM-1, -2, and -3 (Fig. 1B). Although not shown, ICAM expression levels on tumor cells were not affected by pamidronate-pulsing. T cells and ICAM-1^high EJ-1 tumor cells either mock treated or pulsed with pamidronate formed significant cellular conjugates by 30 min after the mixture (Fig. 2A). The conjugate formation with untreated EJ-1 cells was only transient and dissolved nearly to the background level in 2 h. On the other hand, the cellular conjugates between T cells and pamidronate-pulsed EJ-1 cells lasted stably at least for 2 h (Fig. 2A). Inclusion of a blocking anti-LFA-1 mAb in the cocultures of T cells and pamidronate-pulsed EJ-1 cells significantly inhibited the conjugate formation and subsequent IFN- production as well (Fig. 2B). These results strongly suggested that LFA-1/ICAM-1-mediated adhesive interaction with pamidronate-pulsed human tumor cells was one of the requirements for effective activation of T cells.

View larger version (22K): [in this window] [in a new window]   FIGURE 1. Expression of LFA-1 on human T cells and ICAMs on human tumor cell lines. A, Two-color staining of freshly isolated normal PBMC with anti-TCR V2 and anti-LFA-1 mAb (upper) or NKI-L16 mAb specific for an activated form of LFA-1 (lower). B, Staining of representative human tumor cell lines capable of strongly activating human T cells with pamidronate (EJ-1, VMRC-RCW, and K562) and those with poor or no activity to stimulate T cells (LK-2 and MKN45) with anti-ICAM-1, -2, and -3 (bold lines). Fine lines indicate control staining.

View larger version (36K): [in this window] [in a new window]   FIGURE 2. LFA-1-dependent conjugate formation between human T cells and pamidronate-pulsed EJ-1 tumor cells and T cell activation. A, CFSE-labeled T cells and PKH26-labeled EJ-1 tumor cells either unpulsed () or pulsed with 0.1 mM pamidronate (•) were mixed at 37°C for indicated periods and were two-color analyzed by FACScan. Percent conjugated cells represent the percentage of double-positive T cells divided by total T cells. A bar indicates background value of the mixture with no prior incubation. B, Similarly labeled T cells and EJ-1 tumor cells pulsed with 0.1 mM pamidronate were incubated at 37°C for 2 h in the absence () or presence () of anti-LFA-1 Ab (40 µg/ml), and percent conjugated cells were determined as above. A bar indicates background value of the mixture with no prior incubation. The experiments were repeated twice with identical results. C, T cells and EJ-1 tumor cells mock treated (left) or pulsed with 0.1 mM pamidronate were incubated at 37°C for 2 h in the absence (middle) or presence (right) of anti-LFA-1 Ab (40 µg/ml), and IFN--producing cells were determined by two-color staining. Proportions of IFN--producing T cells are indicated.

LFA-1/ICAM-mediated adhesive interaction is necessary but not sufficient for T cell activation by pamidronate-pulsed human tumor cells

These results raised a possibility that failure of T cell activation by a minor population of human tumor cell lines pulsed with pamidronate was due to the insufficient expression of ICAM-1 on the cell surface. To examine this, we transfected a human ICAM-1 cDNA into ICAM-1^low LK-2 and MKN45 cells, which induced only weak or no detectable activation in T cells (see Fig. 1B and Table I), and established ICAM-1^high clones (Fig. 3Aa). A pamidronate-pulsed ICAM-1^high LK-2 clone induced a much stronger activation of T cells than wild-type cells in terms of both IFN- production and specific proliferation (Fig. 3A, b-d). The results confirmed that inefficient activation of T cells by pamidronate-pulsed LK-2 tumor cells was primarily due to the low expression of ICAM-1. In quite a contrast, an ICAM-1^high MKN45 clone pulsed with pamidronate remained defective in activating T cells (Fig. 3B). Essentially the same results were obtained by using other independent ICAM-1^high MKN45 clones. Thus, it was suggested that LFA-1/ICAM-mediated interaction was required but not sufficient for the effective activation of human T cells by tumor cells pulsed with pamidronate.

View larger version (24K): [in this window] [in a new window]   FIGURE 3. Effect of ICAM-1 cDNA transfection into the ICAM-1low human tumor cell lines on the capacity to activate T cells upon treatment with pamidronate. LK-2 (A) and MKN45 (B) tumor cell lines were transfected with ICAM-1 cDNA and analyzed for ICAM-1 expression (a). Dotted lines, control; solid lines, wild-type tumor cells stained with anti-ICAM-1; and bold line, transfected clones stained with anti-ICAM-1 mAb. Human T cells were incubated with the transfectants mock treated (b) or pulsed with 0.1 mM pamidronate (c) for 4 h, and IFN--producing cells were determined. Human T cells (105 cells/well) were cocultured with varying numbers of wild-type tumor cells () or ICAM-1 transfectants (•) pulsed with 0.1 mM pamidronate for 2 days, and the proliferation was assessed. The means and SE of triplicate cultures are indicated.

Expression of human ICAM-1 does not confer the capacity of activating human T cells to murine tumor cell lines

We finally examined the effect of human ICAM-1 expression on murine tumor cell lines. A mouse B16 melanoma clone transfected with human ICAM-1 cDNA (hICAM-1^high B16) expressed a high level of human ICAM-1 comparable to that of EJ-1 human tumor cells (Fig. 4A). However, hICAM-1^high B16 cells pulsed with pamidronate failed to activate human T cells with respect to either IFN- production or specific proliferation (Fig. 4, B and C). In addition, human ICAM-1^high B16 cells pulsed with pamidronate remained totally resistant to cytotoxicity elicited by human T cells (data not shown). Identical results were obtained using hICAM-1^high P3U1 mouse myeloma clones (data not shown). These results strongly suggested that the lack of human T cell activation by pamidronate-pulsed tumor cells of nonhuman origins was not only due to the defective LFA-1/ICAM-1-mediated interaction with human T cells, but also to the absence of additional human-specific element(s) for the effective activation.

View larger version (16K): [in this window] [in a new window]   FIGURE 4. Effect of human ICAM-1 cDNA transfection into a mouse tumor cell line on the activation of human T cells by the treatment with pamidronate. The murine B16 melanoma cell line was transfected with human ICAM-1 cDNA. A, Expression of human ICAM-1. Dotted lines, control; solid lines, wild-type tumor cells stained with anti-hICAM-1; and bold line, transfected clone stained with anti-hICAM-1. B, Human T cells were incubated with transfectants untreated (left) or pulsed with 0.1 mM pamidronate (right) for 4 h, and IFN--producing cells were determined. C, Human T cells (105 cells/well) were cocultured with varying numbers of the wild-type tumor cells () or ICAM-1 transfectants (•) pulsed with 0.1 mM pamidronate for 2 days, and the proliferation was assayed.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

The present results indicated that the majority of pamidronate-pulsed human tumor cell lines of varying tissue origins (21of 26 lines) activated T cells, whereas none of the tumor cell lines of nonhuman origins could activate human T cells (0 of 33 lines). After the pulsing procedure, no significant toxicity was detected in all of the tumor cell lines of both human and nonhuman origins as judged by propidium iodide staining. Thus, it was unlikely that T cells were activated simply by pamidronate nonspecifically bound to the target tumor cells. Incidentally, the present results also suggested that most human V2V2 T cells could not recognize xenogeneic MHC Ags, while human T cells were shown to recognize xenogenic MHC Ags directly and exhibit comparable levels of responses to allogeneic cells (16).

Human T cells highly expressed LFA-1 molecules on their cell surface, and ICAM-1 was detected on most of the human tumor cell lines that could present pamidronate. Then, T cells formed tight conjugates with the pamidronate-pulsed tumor cells. Inclusion of a blocking anti-LFA-1 mAb in the cocultures significantly inhibited the conjugate formation, resulting in the inhibition of IFN- production by T cells. The results suggested that LFA-1/ICAM-1-mediated adhesive interaction was required for effective T cell activation. Consistently, ICAM-1^low LK-2 lung tumor cell line gained a strong capacity of activating T cells by ICAM-1 cDNA transfection upon pretreatment with pamidronate. Although cell clusters between T cells and mock-treated tumor cells were only transient, T cells formed stable conjugates with pamidronate-pulsed tumor cells, lasting for at least 2 h. In T cells, it is indicated that LFA-1 is activated and reorganized to form stable immunological synapse with APC via "inside-out" signaling mediated by TCR (17, 18, 19, 20). In analogy, we speculate that the TCR signaling via cell-associated pamidronate may induce reorganization of LFA-1 to form stable synapse with the Ag-presenting tumor cells.

The present results further indicated that the integrin-mediated interaction was not sufficient for pamidronate-pulsed tumor cells to activate human T cells. Thus, a high level of ICAM-1 expression by cDNA transfection failed to confer the capacity of T cell activation to the ICAM-1^low MKN45 human tumor cell line. Furthermore, expression of human ICAM-1 in murine tumor cell lines could not induce the capacity to activate human T cells at all. These results strongly suggested that additional specific interaction other than integrin-mediated adhesion was required for T cell activation by pamidronate-pulsed tumor cells.

Although the exact nature of interaction between T cells and pamidronate-presenting cells remains to be investigated, at least two possible models are considered, which are not exclusive to each other. First, although the TCR may directly interact with the native nonpeptide Ags presented on the target cells, additional costimulatory signals via specific ligands may be needed for the efficient TCR signaling like the B7 family molecules in the case of T cell activation (21, 22). Although human T cells express a significant level of CD28 (our unpublished data), few tumor cell lines exhibit B7-1 or B7-2 expression, and the candidate molecules remain to be identified. Alternatively, TCR may recognize nitrogen-containing bisphosphonate Ags only in association with specific molecules on the Ag-presenting tumor cells. Our unpublished results indicated that, in addition to the J1.2-encoded lysine residues (11), at least two more additional residues in the putative Ag-binding pocket in V2J1.2V2 TCR were required for T cell activation by diverse nonpeptide Ags (S. Yamashita, Y. Tanaka, and N. Minato, manuscript in preparation). Thus, it is possible that nonpeptide Ags along with specific Ag-presenting molecules optimally fit to the pocket via anchoring residues in much the same way as peptide Ags in complex with MHC molecules for TCR. A number of previous studies provided no evidence for involvement of MHC in T cell activation by nonpeptide Ags (14, 23, 24) and again the candidate molecules remain to be seen.

The present results strongly support the hypothesis that effective activation of human T cells by nonpeptide Ags depends on the immunological synapse formation in which species-specific interactions take place. Nitrogen-containing bisphosphonate Ags are particularly intriguing, in that the vast majority of human tumor cells can efficiently present them to T cells, resulting in the targeted lysis of tumor cells by T cells. It is suggested that the putative molecules required for Ag presentation and effective T cell activation are rather ubiquitously expressed on many human tumor cells. Molecular understanding of the interaction may provide a new clue for potential immunotherapy of human malignancy by targeting tumor cells with chemically defined nonpeptide Ags for T cells.

	Footnotes

 
¹ This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Culture, Sports, and Technology, Japanese government.

² Address correspondence and reprint requests to Dr. Nagahiro Minato, Department of Immunology and Cell Biology, Graduate School of Biostudies, Kyoto University, Yoshida-Konoe-Cho, Sakyo-ku, Kyoto 606-8501, Japan. E-mail address: minato{at}imm.med.kyoto-u.ac.jp

³ Abbreviation used in this paper: h, human.

Received for publication November 25, 2002. Accepted for publication January 31, 2003.

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