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Cutting Edge: Critical Role of NK1⁺ T Cells in IL-12-Induced Immune Responses In Vivo¹

Toshihiko Kawamura², Kazuyoshi Takeda^2,3,*,, Sanjeev K. Mendiratta, Hiroki Kawamura, Luc Van Kaer, Hideo Yagita^*,, Toru Abo and Ko Okumura^*,

Department of Immunology, Niigata University School of Medicine, Niigata, Japan; ^* Department of Immunology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan; Core Research for Evolutional Science and Technology (CREST) of Japan Science and Technology (JST) Corporation, Tokyo, Japan; and Howard Hughes Medical Institute, Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232

	Abstract

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CD1-dependent NK1⁺ T cells rapidly produce IL-4 upon stimulation through the TCR. These cells may therefore play an important role in the initiation of Th2 responses. Here, we show that NK1⁺ T cells constitutively express receptors for IL-12 and IFN-, and that IL-12 induces production of perforin in these cells. Moreover, while IL-12 induces high levels of IFN- and cytotoxic activity of hepatic or splenic mononuclear cells against tumor cells, this effect of IL-12 is significantly reduced in CD1-deficient mice with impaired NK1⁺ T cells development. These results indicate that NK1⁺ T cells play a critical role in IL-12-induced production of IFN- to initiate Th1 immune responses and as IL-12-induced cytotoxic effector cells to initiate antitumor immunity.

	Introduction

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NK1⁺ T cells constitute a unique subset among mature CD4^-8^- and CD4⁺8^- T lymphocytes that coexpress the NK1.1 Ag (1, 2, 3). These cells are abundant in the liver, bone marrow, and thymus but relatively rare in lymph node and spleen (1, 2, 3). The most remarkable feature of NK1⁺ T cells is their highly skewed TCR repertoire. NK1⁺ T cells use a single invariant TCR -chain composed of V14 rearranged to J281 and, predominantly, three TCR Vß (Vß 8.2, Vß 7, and Vß 2) (4, 5, 6). This highly restricted TCR on NK1⁺ T cells presumably recognizes a conserved ligand. Impaired NK1⁺ T cell development in CD1-deficient mice has been recently reported (7, 8, 9), which is consistent with the positive selection of NK1⁺ T cell by CD1-expressing bone marrow-derived cells (10).

The physiologic function of NK1⁺ T cells remains obscure. NK1⁺ T cells were reported to be LAK cells or their precursors (11, 12), and we also reported that NK1⁺ T cells were the major cytotoxic effector responsive to IL-12 (13, 14, 15). On the other hand, NK1⁺ T cells have recently been noted for their unique feature of secreting a large amount IL-4 promptly after CD3 stimulation (16, 17). It was reported that the failure to produce IL-4 and IgE in response to anti-IgD Ab injection in SJL mice and ß₂-microglobulin-deficient mice was linked to their deficiency in IL-4-producing NK1⁺ T cells (18, 19). This correlation has led to the suggestion that IL-4-producing NK1⁺ T cells may play a critical role in the initiation of Th2 responses (20), while others have demonstrated that they also produced IFN- as well as macrophage inflammatory protein-1/ß and lymphotactin (3, 21).

To substantiate the role of NK1⁺ T cells in the response to IL-12 administration, we analyzed the expression of IL-12 and IFN- receptors and the induction of cytolytic molecules in NK1⁺ T cells. We also investigated the IL-12 responsiveness of CD1-deficient mice, which are impaired in the development of NK1⁺ T cells. Our present results substantiated a critical contribution of NK1⁺ T cells to IL-12-induced IFN- production and cytotoxicity in vivo.

	Materials and Methods

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Mice

Male C57BL/6 (B6) mice, 6 wk of age, were purchased from Clear Japan Inc. (Tokyo, Japan). CD1-deficient mice were generated by targeted disruption of the CD1d1 gene (9). Homozygous (-/-) or control (+/+) (B6 x 129/Sv) F3 mice were used at 8 wk of age in this study.

In vivo cell depletion

Polyclonal rabbit anti-asialo GM1 (AsGM1) Ab (Wako Co., Tokyo, Japan) (30 µg/mice) was i.v. injected into mice 3 day before IL-12 administration, to eliminate NK cells.

Cell preparation

Splenic mononuclear cells (MNC)⁴ and hepatic MNC were prepared as previously described (13).

IL-12

Recombinant murine IL-12 (4.9 x 10⁶U/mg) was kindly provided by Genetics Institute Inc. (Andover, MA). The preparation was diluted in PBS immediately before use.

Immunofluorescence and cell sorting

The surface phenotype of the cells was identified by two-color flow cytometry as described previously (13). To block Fc binding, cells were preincubated with anti-mouse CD32/16 (2.4G2) mAb before staining. The mAbs used were FITC-conjugated anti-mouse CD3 (145-2C11) and phycoerythrin-conjugated anti-NK1.1 (PK 136). All mAbs were obtained from PharMingen (San Diego, CA). Flow cytometric analysis was conducted on a FACScan (Becton Dickinson Co., San Jose, CA). For sorting, a FACS Vantage (Becton Dickinson) was used.

Reverse transcription (RT)-PCR

Total cellular RNA was extracted from 2 x 10⁵ freshly sorted cells. Single-stranded cDNA was synthesized with reverse transcriptase from serial dilutions of RNA and then used for PCR reaction as previously described (22). The primers for V14, C, ß-actin, IL-12R ß 1, IFN-R, perforin, and FasL were adopted from previous reports (5, 22, 23, 24, 25). The primers for Cß and IL-12Rß2 have the following sequences: Cß, 5' primer-AGGATCTGAGAAATGTGACT and 3' primer-GACCATGGCCATCAGCACTA; IL-12Rß2, 5' primer-GAGTACATAGTGGAATGGAGAG and 3' primer-TCACAGCTGTCATCCATAGGAC. ß-actin was used both as internal control and as a standard to compare the amount of mRNA used for PCR amplification.

Cytotoxicity assay

Cytolytic activity was assessed against YAC-1 (NK-susceptible target) and P815 (NK-resistant target) by a standard ⁵¹Cr release assay (13). Briefly, after 4 h of mixed incubation of 5 x 10^{3 51}Cr-labeled target cells and serial dilutions of effector cells, supernatants were harvested and counted with a gamma counter. The spontaneous release was less <15% of the maximum release.

Enzyme-linked immunosorbent assay

Serum IFN- levels were evaluated using a specific ELISA kit for mouse IFN- (Amersham, Buckinghamshire, England).

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
NK1⁺ T cells constitutively express receptors for IL-12 and IFN-

We previously reported that NK1⁺ T cells were the predominant effector cells responsible for IL-12-induced cytotoxicity in vivo (13, 14, 15). To confirm and further extend these findings, we evaluated the expression of receptors for IL-12 and IFN- on NK1⁺ T cells. Hepatic MNC, which contain abundant numbers of NK1⁺ T cells, were separated into NK (NK1⁺ CD3^-) cells, NK1⁺ T (NK1⁺ CD3⁺) cells, and T (NK1^- CD3⁺) cells by FACS sorting. The purity of these populations was >99% as estimated by FACS reanalysis (data not shown). Furthermore, RT-PCR analysis for V14, TCR -chain (C), and TCR ß-chain (Cß) expression showed that C and Cß could not be detected in the NK cell population and that V14 was only detected in the NK1⁺ T cell population (Fig. 1A). We then examined the expression of IL-12 and IFN- receptors in these populations by semiquantitative RT-PCR analysis. As represented in Figure 1B, NK1⁺ T cells expressed IL-12Rß1 and -ß2 and IFN-R more abundantly than NK cells, while IL-12Rß1 and -ß2 were not detectable in NK1^- T cells. These results indicate that NK1⁺ T cells are the predominant population that expresses IL-12R among hepatic MNC.

View larger version (21K): [in this window] [in a new window]   FIGURE 1. Expression of IL-12R, IFN-R, perforin, and FasL in NK1+ T cells. A, Selective expression of V14. Hepatic MNC from normal B6 mice were stained with anti-NK1.1 and anti-CD3 mAbs and separated into NK1+ CD3- (NK), NK1+ CD3+ (NK1+ T) and NK1- CD3+ (T) cell populations. mRNA was extracted from each population, and RT-PCR analysis was performed with primers specific for C, Cß, V14, and ß-actin. B, Constitutive expression of IL-12 and IFN- receptors. The mRNA from each population was serially diluted and analyzed by semiquantitative RT-PCR with primers specific for IL-12 Rß1, ß2, IFN- R, and ß-actin. Data represent the dilution point at which the RT-PCR signal was proportional to the amount of RNA. C, Induction of perforin by IL-12. Hepatic MNC were prepared from B6 mice 24 h after i.p. injection of PBS or IL-12 (1000 U) and separated as above, and mRNA was prepared from each population. Semiquantitative RT-PCR was performed with primers specific for perforin, FasL, and ß-actin. Data represent the dilution point at which the RT-PCR signal was proportional to the amount of mRNA.

To corroborate our earlier finding that IL-12 induces the cytotoxic activity of NK1⁺ T cells (13, 14, 15), we examined the expression of perforin and FasL mRNA in these cells. Hepatic MNC prepared from IL-12-injected mice were separated into NK, NK1⁺ T, and T cells as described above, and the purity of these cells was verified by FACS and RT-PCR analysis (data not shown). FasL mRNA was constitutively expressed in both NK and NK1⁺ T cells and was not significantly increased by IL-12 injection. In contrast, the expression of perforin mRNA was remarkably augmented in NK1⁺ T cells by IL-12 to levels larger than in NK cells (Fig. 1C). No perforin or FasL mRNA induction was observed in NK1^- T cells. These results suggest that the induction of perforin may be responsible for the IL-12-induced cytotoxic activity of NK1⁺ T cells.

IL-12-induced cytotoxicity and serum IFN- are impaired in CD1-deficient mice

To provide further evidence for the role of NK1⁺ T cells in IL-12-induced immune responses, we administrated IL-12 to CD1-deficient mice that impaired NK1⁺ T cells. NK1⁺ T cells were greatly diminished among hepatic MNC from CD1-/- mice, as previously reported (9), and IL-12 administration did not affect the composition of MNC subsets (Fig. 2). In contrast, the percentage of NK cells in CD1-/- mice was equivalent to control mice. NK1⁺ T cells were also selectively impaired among splenic MNC (data not shown). The IL-12-induced cytotoxic activity against both NK-susceptible (YAC-1) and NK-resistant (P815) target cells was obviously reduced in CD1-deficient mice (Fig. 3). The cytotoxic activity of hepatic MNC, which contained more NK1⁺ T cells, was more dramatically reduced than that of splenic MNC. IL-12-induced serum IFN- levels were also greatly reduced in CD1-deficient mice to about one-third of that in control mice (Fig. 4). To characterize the cell population involved in the residual IL-12-induced immune responses in CD1-deficient mice, anti-AsGM1 Ab was administrated to deplete NK cells (Fig. 2). The residual IL-12-induced cytotoxicity and serum IFN- in CD1-/- mice was almost completely abolished by the NK cell depletion (Figs. 3 and 4). These results indicate that NK1⁺ T cells are the predominant mediator of IL-12-induced cytotoxicity and IFN- production in vivo, although a minor contribution from NK cells was also noted.

View larger version (44K): [in this window] [in a new window]   FIGURE 2. Selective impairment of NK1+ T cells in CD1-deficient mice. Hepatic MNC were prepared from CD1+/+, CD1 -/-, or anti-AsGM1-treated CD1-/- mice 24 h after i.p. injection of IL-12 (1000 U) or PBS and stained with anti-NK1.1 and anti-CD3 mAbs. The percentages of NK cells and NK1+ T cells (boxed) are indicated in each panel.

View larger version (24K): [in this window] [in a new window]   FIGURE 3. Impairment of IL-12-induced cytotoxicity in CD1-deficient mice. CD1+/+, CD1 -/-, or anti-AsGM1-treated CD1-/- mice were i.p. injected with PBS or IL-12 (1000 U), and the splenic and hepatic MNC were prepared 24 h later. Cytotoxicity against YAC-1 (A) and P815 (B) were tested at the indicated E:T ratios. Data shown are representative of three independent experiments with similar results.

View larger version (12K): [in this window] [in a new window]   FIGURE 4. Impairment of IL-12-induced serum IFN- in CD1-deficient mice. Serum samples were obtained from CD1+/+, CD1 -/-, or anti-AsGM1-treated CD1-/- mice at 24 h after IL-12 (1000 U) injection. Data are shown as the mean ± SD from three mice in each group (p < 0.01). Serum IFN- in the PBS-injected mice was not detectable (not shown).

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

Recently, several groups have reported that IL-4-secreting NK1⁺T cells are not required to elicit Th2 responses and IgE production, although prompt IL-4 secretion in response to anti-CD3 Ab injection was totally impaired in CD1-deficient mice (7, 8, 9). In addition, we observed that IFN- production in response to anti-CD3 Ab injection was also greatly reduced in CD1-deficient mice (9). This observation is consistent with the present results, although the stimulation was different. In the present experiments, IL-12-induced cytotoxicity and increase of serum IFN- were not completely eliminated in the CD1-deficient mice. This residual IL-12 responses were due to the response of NK cells to IL-12, although their expression of IL-12R was considerably lower than that of NK1⁺ T cells (Fig. 1B). Nevertheless, the large amount of IL-12 injected into the CD1-deficient mice might be sufficient to activate NK cells to overcome the impairment of NK1⁺T cells, which might be preferentially activated by lower doses of IL-12. Therefore, NK1⁺T cells would be the major IL-12-responding cells in vivo, especially in the response to minute amounts of IL-12.

Consistent with our detection of FasL mRNA in NK1⁺ T cells, Arase et al. reported that NK1⁺ T cells exert FasL-mediated cytotoxicity (26). We observed that IL-12-activated NK1⁺ T cells demonstrated MHC-unrestricted cytotoxicity against Fas-negative and/or CD1-negative targets, which could not be inhibited by anti-TCRß mAb or anti-NK1.1 mAb (our unpublished observation). We also found that the IL-12-induced cytotoxicity was retained in FasL-deficient gld mice (our unpublished observation). Therefore, when NK1⁺ T cells are stimulated by IL-12, they are induced to express perforin and can lyse even Fas^- target cells independently of TCR-mediated recognition of CD1.

Several lines of evidence indicate that NK1⁺ T cells can promote both Th1 and Th2 responses, depending on how they are stimulated. First, NK1⁺ T cells secrete a large amount of IFN- when stimulated through NK1.1 or by IL-12, while they secrete IL-4 by CD3 cross-linking in vitro (21). Second, NK1⁺ T cells are involved in the generation of CD8⁺ effector cells against intracellular bacterial infection in MHC class II-deficient mice (27). Finally, we have previously shown that Con A injection induces prompt IL-4 secretion by NK1⁺ T cells in the liver, thus promoting the onset of Con A-induced hepatitis (28). It is likely, therefore, that NK1⁺ T cells are bipotential cells that can initiate not only Th2-type but also Th1-type immune responses, depending largely on the stimuli they encounter in the initial phase of an immune response. TCR-mediated recognition of CD1 would result in IL-4 production to initiate humoral immunity. On the other hand, a stimulatory signal that interacts with NK1.1- or APC-derived IL-12 would activate NK1⁺ T cells to produce IFN-, thus promoting cell-mediated immunity. Alternatively, it remains still possible that distinct subsets of NK1⁺ T cells produce IL-4 and IFN-. To elucidate the physiologic role of NK1⁺ T cells, further studies on the physiologic stimuli that provoke preferential secretion of IL-4 or IFN- by NK1⁺ T cells will be needed.

	Footnotes

 
¹ This work was supported by a grant-in-aid for Scientific Research from the Ministry of Education, Science, and Culture, Japan.

² The first two authors equally contributed to this work.

³ Address correspondence and reprint requests to Dr. Kazuyoshi Takeda, Department of Immunology, Juntendo University School of Medicine, 2-1-1 Hongo, Bukyou-ku, Tokyo 113, Japan. E-mail address:

⁴ Abbreviations used in this paper: MNC, mononuclear cells; Fas L, Fas ligand; AsGM1, asialo-GM1; RT-PCR, reverse transcription PCR.

Received for publication August 22, 1997. Accepted for publication October 23, 1997.

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				D. Stober, I. Jomantaite, R. Schirmbeck, and J. Reimann NKT Cells Provide Help for Dendritic Cell-Dependent Priming of MHC Class I-Restricted CD8+ T Cells In Vivo J. Immunol., March 1, 2003; 170(5): 2540 - 2548. [Abstract] [Full Text] [PDF]

				M. Araki, T. Kondo, J. E. Gumperz, M. B. Brenner, S. Miyake, and T. Yamamura Th2 bias of CD4+ NKT cells derived from multiple sclerosis in remission Int. Immunol., February 1, 2003; 15(2): 279 - 288. [Abstract] [Full Text] [PDF]

				S.-H. Park, T. Kyin, A. Bendelac, and C. Carnaud The Contribution of NKT Cells, NK Cells, and Other {gamma}-Chain-Dependent Non-T Non-B Cells to IL-12-Mediated Rejection of Tumors J. Immunol., February 1, 2003; 170(3): 1197 - 1201. [Abstract] [Full Text] [PDF]

				J. G. Segal, N. C. Lee, Y. L. Tsung, J. A. Norton, and K. Tsung The Role of IFN-{gamma} in Rejection of Established Tumors by IL-12 : Source of Production and Target Cancer Res., August 15, 2002; 62(16): 4696 - 4703. [Abstract] [Full Text] [PDF]

				N. Y. Crowe, M. J. Smyth, and D. I. Godfrey A Critical Role for Natural Killer T Cells in Immunosurveillance of Methylcholanthrene-induced Sarcomas J. Exp. Med., July 1, 2002; 196(1): 119 - 127. [Abstract] [Full Text] [PDF]

				M. J. Smyth, N. Y. Crowe, D. G. Pellicci, K. Kyparissoudis, J. M. Kelly, K. Takeda, H. Yagita, and D. I. Godfrey Sequential production of interferon-gamma by NK1.1+ T cells and natural killer cells is essential for the antimetastatic effect of alpha -galactosylceramide Blood, February 15, 2002; 99(4): 1259 - 1266. [Abstract] [Full Text] [PDF]

				K. Adachi, H. Tsutsui, S.-I. Kashiwamura, E. Seki, H. Nakano, O. Takeuchi, K. Takeda, K. Okumura, L. Van Kaer, H. Okamura, et al. Plasmodiumberghei Infection in Mice Induces Liver Injury by an IL-12- and Toll-Like Receptor/Myeloid Differentiation Factor 88-Dependent Mechanism J. Immunol., November 15, 2001; 167(10): 5928 - 5934. [Abstract] [Full Text] [PDF]

				S. Muhammad Ali Tahir, O. Cheng, A. Shaulov, Y. Koezuka, G. J. Bubley, S. B. Wilson, S. P. Balk, and M. A. Exley Loss of IFN-{gamma} Production by Invariant NK T Cells in Advanced Cancer J. Immunol., October 1, 2001; 167(7): 4046 - 4050. [Abstract] [Full Text] [PDF]

				C. Karnbach, M. R. Daws, E. C. Niemi, and M. C. Nakamura Immune Rejection of a Large Sarcoma Following Cyclophosphamide and IL-12 Treatment Requires Both NK and NK T Cells and Is Associated with the Induction of a Novel NK T Cell Population J. Immunol., September 1, 2001; 167(5): 2569 - 2576. [Abstract] [Full Text] [PDF]

				M. A. Exley, N. J. Bigley, O. Cheng, S. M. A. Tahir, S. T. Smiley, Q. L. Carter, H. F. Stills, M. J. Grusby, Y. Koezuka, M. Taniguchi, et al. CD1d-reactive T-cell activation leads to amelioration of disease caused by diabetogenic encephalomyocarditis virus J. Leukoc. Biol., May 1, 2001; 69(5): 713 - 718. [Abstract] [Full Text]

				M. J. Smyth, N. Y. Crowe, and D. I. Godfrey NK cells and NKT cells collaborate in host protection from methylcholanthrene-induced fibrosarcoma Int. Immunol., April 1, 2001; 13(4): 459 - 463. [Abstract] [Full Text] [PDF]

				R. B. Fritz and M.-L. Zhao Regulation of Experimental Autoimmune Encephalomyelitis in the C57BL/6J Mouse by NK1.1+, DX5+, {{alpha}}{{beta}}+ T Cells J. Immunol., March 15, 2001; 166(6): 4209 - 4215. [Abstract] [Full Text] [PDF]

				M. J. Smyth, E. Cretney, K. Takeda, R. H. Wiltrout, L. M. Sedger, N. Kayagaki, H. Yagita, and K. Okumura Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) Contributes to Interferon {{gamma}}-dependent Natural Killer Cell Protection from Tumor Metastasis J. Exp. Med., March 12, 2001; 193(6): 661 - 670. [Abstract] [Full Text] [PDF]

				S. E. A. Street, E. Cretney, and M. J. Smyth Perforin and interferon-{gamma} activities independently control tumor initiation, growth, and metastasis Blood, January 1, 2001; 97(1): 192 - 197. [Abstract] [Full Text] [PDF]

				F. Dieli, G. Sireci, D. Russo, M. Taniguchi, J. Ivanyi, C. Fernandez, M. Troye-Blomberg, G. De Leo, and A. Salerno Resistance of Natural Killer T Cell-deficient Mice to Systemic Shwartzman Reaction J. Exp. Med., December 4, 2000; 192(11): 1645 - 1652. [Abstract] [Full Text] [PDF]

				S. Adris, E. Chuluyan, A. Bravo, M. Berenstein, S. Klein, M. Jasnis, C. Carbone, Y. Chernajovsky, and O. L. Podhajcer Mice Vaccination with Interleukin 12-transduced Colon Cancer Cells Potentiates Rejection of Syngeneic Non-Organ-related Tumor Cells Cancer Res., December 1, 2000; 60(23): 6696 - 6703. [Abstract] [Full Text]

				K. J. Andrews, A. Ribas, L. H. Butterfield, C. M. Vollmer, F. C. Eilber, V. B. Dissette, S. D. Nelson, P. Shintaku, S. Mekhoubad, T. Nakayama, et al. Adenovirus-Interleukin-12-mediated Tumor Regression in a Murine Hepatocellular Carcinoma Model Is Not Dependent on CD1-restricted Natural Killer T Cells Cancer Res., November 1, 2000; 60(22): 6457 - 6464. [Abstract] [Full Text]

				G. E. Plautz, S. Mukai, P. A. Cohen, and S. Shu Cross-Presentation of Tumor Antigens to Effector T Cells Is Sufficient to Mediate Effective Immunotherapy of Established Intracranial Tumors J. Immunol., October 1, 2000; 165(7): 3656 - 3662. [Abstract] [Full Text] [PDF]