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Differential Roles of Cytokine Receptors in the Development of Epidermal T Cells¹

Sang-Kyu Ye^*, Kazushige Maki^2,*, Hai-Chon Lee^*, Akiko Ito, Kazuhiro Kawai, Haruhiko Suzuki, Tak W. Mak, Yueh-hsiu Chien^¶, Tasuku Honjo^* and Koichi Ikuta^3,*

^* Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Dermatology, Niigata University School of Medicine, Niigata, Japan; Department of Immunology, Graduate School of Medicine, Nagoya University, Nagoya, Japan; Amgen Institute, Toronto, Ontario, Canada; and ^¶ Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion References

 
IL-7 and IL-15 play important roles in T cell development. These receptors transmit proliferation and/or survival signals in T cells. In addition, the IL-7R promotes recombination and transcription in the TCR locus. To clarify the role of the cytokine receptors in the development of epidermal T cells, we introduced a V3/V1 TCR transgene, derived from Thy-1⁺ dendritic epidermal T cells (DETC), into IL-7R-deficient mice, and we found that they partly rescued T cells in the adult thymus but not in the spleen. Introduction of an additional Bcl-2 transgene had a minimal effect on T cells in the adult thymus of these mice. In contrast to the adult thymus, the introduction of the V3/V1 TCR transgene into IL-7R^-/- mice completely restored V3⁺ T cells in the fetal thymus and DETC in the adult skin. On the contrary, the same V3/V1 TCR transgene failed to rescue DETC in the skin of IL-2R-deficient mice, even with the additional Bcl-2 transgene. These results suggest that the IL-2/IL-15R, rather than the IL-7R, plays an essential role in proliferation and survival of DETC in the fetal thymus and the skin. In contrast, the IL-7R is probably essential in the induction of V-J recombination of TCR genes. Thus, this study proves that IL-7R and IL-2/IL-15R serve differential functions in epidermal T cell development.

	Introduction

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Development of T cells has unique features in contrast to T cell development (1, 2, 3). T cells expressing a specific V -chain appear as several successive waves in the developing thymus, and each of them shows distinct tissue distribution in the adult mouse. V3⁺ T cells develop as the first wave in the fetal thymus and become Thy-1⁺ dendritic epidermal T cells (DETC)⁴ in the adult skin. V4⁺ T cells are the second wave and are distributed in the epithelium of the lung, tongue, and vagina. These two epithelial T cell subsets express homogeneous TCRs, V3/V1 or V4/V1, with a single species of V-J junctional sequence. V2⁺ T cells develop in the thymus after these cells and reside mainly in the spleen and the lymph nodes. In contrast, the majority of intestinal intraepithelial lymphocytes (IEL) express V5 TCR and develop in the gut from cryptopatches (4, 5). This sequential development of T cells is regulated by the V-J recombination of the TCR locus (6) and is predetermined at the level of hematopoietic stem cells (7, 8).

IL-7 is an essential cytokine for T cell development. IL-7 exerts its effect through interaction with the IL-7R, which is composed of a unique -chain (IL-7R) and the common cytokine receptor -chain (_c) (9). Recently, thymic stromal lymphopoietin has been shown to transmit signals through IL-7R and thymic stromal lymphopoietin receptor heterodimer (10, 11). Injection of neutralizing Abs to IL-7 or IL-7R or genetic ablation of IL-7, IL-7R, or _c leads to a block of lymphocyte development (12, 13, 14, 15, 16, 17). Although IL-7R-deficient mice have small numbers of B cells and T cells in periphery, they totally lack T cells (18, 19). The IL-7R transmits at least two types of signals in lymphocyte progenitors (20). One signal is for survival and proliferation. For instance, the IL-7R induces the expression of Bcl-2 in T cell precursors (21), and introduction of Bcl-2 transgenes partly restores T cell development in IL-7R-deficient mice (22, 23). The IL-7R supports the proliferation of lymphocyte precursors through the activation of phosphatidylinositol (PI)-3 kinase (24, 25). Peripheral T cells in IL-7R-deficient mice are also defective in survival and proliferation (26). The second signal from the IL-7R is to promote recombination and transcription in the IgH and TCR loci. For example, IL-7R signaling induces germline transcription and DNA rearrangement in D-distal V segments in pro-B cells (27). The V-J recombination and transcription of TCR genes is also severely impaired in IL-7R-deficient mice (28, 29, 30). STAT5, a signaling molecule of the IL-7R, induces germline transcription in the TCR locus and promotes V-J recombination and T cell development (31).

In additon to IL-7, other cytokines play substantial roles in T cell development. IL-15 achieves its effects through interaction with the IL-15R, which is composed of a unique -chain (IL-15R), the common -chain (IL-2R), and the _c (32). Deletion of IL-15, IL-15R, or IL-2R results in a block of NK cell development and impaired T cell development in the epithelium (33, 34, 35). Mature V3⁺ thymocytes in the fetal thymus express IL-2R, and in utero treatment with anti-IL-2R Ab abrogates DETC in the adult skin (36). IL-2R-deficient mice have decreased numbers of IEL (33). These mice also have defective maturation of V3 thymocytes and lack DETC (37). These results suggest that IL-15 plays important roles in the development of IEL and DETC. Besides IL-15, IL-2 is also implicated in thymic and extrathymic T cell development (38).

Both the IL-7R and the IL-2/IL-15R mobilize a similar set of signaling molecules (9). The ligand binding to the receptors triggers the phosphorylation and activation of receptor-associated Janus kinase (Jak)1 and Jak3 tyrosine kinases. Following their activation, the Jak kinases phosphorylate the specific tyrosine residues of IL-7R and IL-2R. The STAT proteins, and PI3 kinase in case of the IL-7R, are recruited to the tyrosine residues and subsequently phosphorylated and activated by the Jak kinases. The receptors mainly activate STAT5A and STAT5B. The phosphorylated STAT5 proteins then form dimers and bind to a consensus motif and activate the transcription of various target genes, including TCR genes. PI3 kinase phosphorylates PI and activates Akt. Akt protein in turn inactivates Bad, caspase-9, and IB kinase- proteins by phosphorylation and transmits antiapoptotic signals. The Jak kinases also activate signal-transducing adaptor molecule and proline-rich tyrosine kinase-2 proteins. This signaling pathway then activates mitogen-activated protein kinase cascade and results in cell proliferation. The IL-7R also induces Bcl-2 expression in early T cells by an unidentified pathway (21).

The roles for each signaling pathway in T cell development are largely unknown. Introduction of a V1.1/V6 TCR transgene failed to restore T cells in _c-deficient mice, suggesting that the IL-7R plays some role in proliferation and/or survival of T cells (39). Introduction of a Bcl-2 transgene partly restored , but not , T cell development in IL-7R-deficient mice (31). Similarly, the Bcl-2 transgene alone did not rescue B cells, T cells, and NK cells in _c-deficient mice (40). However, these experiments did not clarify the role of Bcl-2 in T cell development, because the IL-7R signaling is necessary for the recombination and transcription of TCR genes. To clarify the roles of the cytokine receptors in the development of epidermal T cells, we introduced a V3/V1 TCR transgene into IL-7R-deficient mice and found that they restored V3⁺ T cells in the fetal thymus and the skin. In contrast, the same V3/V1 TCR transgene failed to rescue T cells in the skin of IL-2R-deficient mice. Further addition of a Bcl-2 transgene did not recover epidermal T cells in IL-2R-deficient mice. Thus, this study revealed that IL-7R and IL-2/IL-15R serve differential functions in epidermal T cell development.

	Materials and Methods

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Mice

IL-7R-deficient (18), IL-2R-deficient (41), and H-2K-Bcl-2-transgenic (Tg) mice (42) were reported previously and were bred on the (129/Ola x C57BL/6) hybrid background. The Bcl-2 transgene is driven by a H-2K promoter and expressed on virtually all blood cells. Tg mice containing productively rearranged V3/V1 TCR genes were described before (43) and maintained on the C57BL/6 background. The V3/V1 TCR is derived from a DETC line. The genotype of mice and fetuses was determined by PCR. The age of fetuses was determined by taking the appearance of a vaginal plug as day 0. All mice were maintained under the specific pathogen-free conditions in the Institute of Laboratory Animals at the Graduate School of Medicine, Kyoto University (Kyoto, Japan).

Cell preparations

Thymocytes and spleen cells were harvested in PBS supplemented with 2% FBS and 0.02% sodium azide (FACS solution). RBCs were lysed, and cells were washed in the FACS solution. Epidermal cells were isolated from the ears as previously described but with slight modifications (44). Briefly, the ears were separated into two sides with fine forceps and incubated on PBS containing 1% trypsin for 45 min at 37°C. Epidermal sheets were separated from the dermis with fine forceps. Epidermal cells were released by gently rubbing the sheets with a plastic rod. The viable cells were purified by density gradient centrifugation with Lympholyte-M (Cedarlane Laboratories, Hornby, Onatrio, Canada) and cultured in RPMI 1640 medium containing 10% FBS and 5% conditioned medium of Con A-stimulated rat spleen cells for 24 h.

Abs and flow cytometric analysis

The following mAbs were used: FITC-conjugated Abs 145-2C11(anti-CD3), 53-6.7 (anti-CD8), H57-597 (anti- TCR), 536 (anti-V3/V1 TCR), M1/69 (anti-CD24), and 53-2.1 (anti-Thy-1.2); biotin-conjugated Abs H57-597 (anti- TCR) and M181.1 (anti-V3/V1 TCR); and PE-conjugated Abs GK1.5 (anti-CD4), GL3 (anti- TCR), and 2G9 (anti-I-A^d/I-E^d). The above-mentioned mAbs were purchased from BD PharMingen (San Diego, CA). Biotin-anti-V3/V1 TCR Ab was a gift from Dr. I. MacNeil (Ariad Pharmaceuticals, Cambridge, MA) (7), and PE-streptavidin was obtained from Biomedia (Foster City, CA). Flow cytometric analysis was performed as previously described (31). Debris, erythrocytes, and dead cells were excluded from the analysis by forward and side scatters and propidium iodide gatings. Viable cells were analyzed by a FACSCalibur with CellQuest software version 3.1 (BD Biosciences, San Jose, CA).

Immunofluorescence staining of epidermal sheets

Immunofluorescence staining of epidermal sheets was done as described previously (44). Briefly, the sheets were fixed in cold acetone for 20 min, rinsed in PBS, and incubated with FITC-anti-Thy-1.2 or FITC-anti-V3/V1 TCR Ab for 2 h at room temperature. After rinses in PBS, the sheets were mounted on slide glass and examined under a fluorescence microscope.

	Results

Top Abstract Introduction Materials and Methods Results Discussion References

 
Introduction of a V3/V1 TCR transgene partly restores T cells in the adult thymus of IL-7R-deficient mice

To test the role of the IL-7R in the development of epidermal T cells, we introduced a V3/V1 TCR transgene into the IL-7R-deficient mice to bypass the defective V-J recombination (28, 29). We backcrossed the V3/V1 TCR-Tg mice to IL-7R^-/- mice and chose four genotypes of mice, namely, IL-7R^+/-, V3/V1 TCR-Tg⁺IL-7R^+/-, IL-7R^-/-, and V3/V1 TCR-Tg⁺IL-7R^-/-. Thymocytes and spleen cells were isolated from the mice and analyzed by flow cytometry (Fig. 1). Although only 0.3% of thymocytes expressed TCR in IL-7R^+/- mice, 14% of thymocytes were T cells expressing the V3/V1 TCR transgene in TCR-Tg⁺IL-7R^+/- mice. In TCR-Tg⁺IL-7R^+/- mice, 51% of thymocytes were CD4^-CD8^-, suggesting that many of the Tg T cells were CD4^-CD8^-. In contrast, we did not detect any distinct TCR⁺ cells in IL-7R^-/- mice, as we and others reported previously (18, 19). In TCR-Tg⁺IL-7R^-/- mice, 6.3% of thymocytes were T cells expressing the V3/V1 TCR transgene. These results suggest that the introduction of the V3/V1 TCR transgene alone significantly rescued T cell development in the thymus of IL-7R^-/- mice. In contrast, introduction of the V3/V1 TCR transgene gave rise to much poorer recovery of V3⁺ T cells in the spleen of IL-7R^-/- mice (Fig. 2). A small but distinct V3⁺ T cell population (0.95–2.00% in four mice) constantly developed in the spleen of TCR-Tg⁺IL-7R^+/- mice, although some double-positive signals (0.70–1.70%) were detected, partly due to the appearance of TCR^dull T cells by the effect of the transgene. In contrast, no V3⁺ T cell populations were detected in IL-7R^-/- and TCR-Tg⁺IL-7R^-/- mice.

View larger version (74K): [in this window] [in a new window]   FIGURE 1. Introduction of a V3/V1 TCR transgene partly restores T cells in the thymus of IL-7R-deficient mice. Thymocytes were isolated from IL-7R+/-, TCR-Tg+IL-7R+/-, IL-7R-/-, and TCR-Tg+IL-7R-/- mice. Cells were stained with either FITC-anti-TCR and PE-anti-TCR, FITC-anti-TCR and PE-anti-V3/V1 TCR, or FITC-anti-CD8 and PE-anti-CD4 Abs. The percentages of cells for a given phenotype are shown. The data are representative of three to four mice of each genotype (8- to 10-wk-old littermates). The cell numbers recovered from each mouse are shown above each panel.

View larger version (74K): [in this window] [in a new window]   FIGURE 2. Introduction of the V3/V1 TCR transgene fails to restore T cells in the spleen of IL-7R-deficient mice. Spleen cells were isolated and analyzed as shown in the legend to Fig. 1. The percentages of cells for a given phenotype are shown. The data are representative of three to four mice of each genotype (8- to 10-wk-old littermates). The cell numbers recovered from each mouse are shown above each panel.

View larger version (23K): [in this window] [in a new window]   FIGURE 3. Numbers of total and T cells in the thymus of IL-7R-deficient mice with the V3/V1 TCR and a Bcl-2 transgenes. Numbers of total (A) and T (B) cells were counted in the thymus from IL-7R+/-, TCR-Tg+IL-7R+/-, IL-7R-/-, TCR-Tg+IL-7R-/-, and Bcl-2-Tg+TCR-Tg+IL-7R-/- 8- to 10-wk-old mice. The mean ± SE is calculated from three to four mice. The numbers of T cells were calculated from the total cell numbers and the percentage of T cells in each mouse. *, The Student’s t test for unpaired data was used to compare the values between two groups, and the difference was not significant (p = 0.069).

The V3/V1 TCR transgene restores V3⁺ T cells in the fetal thymus of IL-7R-deficient mice

Because V3⁺ T cells develop as the first wave of T cells in the fetal thymus, we checked E17 fetal thymocytes by flow cytometry (Fig. 4). In IL-7R^+/+ mice, 1.9% of thymocytes were V3⁺. Some of them were V3/V1 TCR⁺CD24^-, suggesting they were at mature stages (45). However, in IL-7R^-/- fetal thymus, few cells expressed V3/V1 TCR, in agreement with the previous observation that IL-7R-deficient mice lack T cells in the fetal thymus (18). On the contrary, 40% of thymocytes were V3⁺ T cells in TCR-Tg⁺IL-7R^-/- fetuses. A part of these Tg T cells were at mature stages expressing V3/V1 TCR⁺CD24^-.

View larger version (53K): [in this window] [in a new window]   FIGURE 4. Introduction of the V3/V1 TCR transgene restores T cells in the fetal thymus of IL-7R-deficient mice. E17 fetal thymocytes were isolated from IL-7R+/+, IL-7R-/-, and V3/V1 TCR-Tg+IL-7R-/- mice. Cells were stained with either FITC-anti-V3/V1 TCR and PE-anti-CD3 or FITC-anti-CD24 and biotin-anti-V3/V1 TCR Abs, followed by PE-streptavidin. The percentages of cells for a given phenotype are shown. The data are representative of three to four E17 fetuses of each genotype. The cell numbers recovered from each mouse are shown above each panel.

View larger version (28K): [in this window] [in a new window]   FIGURE 5. Introduction of the V3/V1 TCR transgene restores the numbers of V3+ T cells in the fetal thymus of IL-7R-deficient mice. Numbers of total and V3+ T cells were counted in E17 fetal thymus from IL-7R+/+, IL-7R-/-, and V3/V1 TCR-Tg+IL-7R-/- mice. The mean ± SE is calculated from three to four fetuses. The numbers of V3+ T cells were calculated from the total numbers and the percentage of V3+ T cells in each fetus.

The V3/V1 TCR transgene restores DETC in the skin of IL-7R-deficient mice

Because these V3⁺ T cells are distributed as DETC in the skin of adult mice (46), we next isolated epidermal cells from IL-7R^+/-, TCR-Tg⁺IL-7R^+/-, IL-7R^-/-, and TCR-Tg⁺IL-7R^-/- mice and analyzed them by flow cytometry (Fig. 6). V3/V1 TCR⁺ DETC were detected in both IL-7R^+/- and TCR-Tg⁺IL-7R^+/- mice. IL-7R^-/- mice lacked these cells, in agreement with the previous observation that IL-7R-deficient mice lack DETC (18). However, TCR-Tg⁺IL-7R^-/- mice contained abundant DETC expressing V3/V1 TCR in the skin. We equally detected MHC class II⁺ Langerhans cells in all of these mice. Similar results were obtained by fluorescence staining of epidermal sheets (data not shown). These results suggest that the IL-7R is probably dispensable for the maintenance of DETC in the skin.

View larger version (29K): [in this window] [in a new window]   FIGURE 6. Introduction of the V3/V1 TCR transgene restores V3+ T cells in the skin of IL-7R-deficient mice. Epidermal cells were isolated from IL-7R+/-, TCR-Tg+IL-7R+/-, IL-7R-/-, and TCR-Tg+IL-7R-/- mice. Cells were stained with FITC-anti-V3/V1 TCR and PE-anti-I-Ad/I-Ed Abs. The percentages of cells for a given phenotype are shown. The data are representative of two 8-mo-old mice of each genotype.

Introduction of the V3/V1 TCR transgene fails to rescue DETC in the skin of IL-2R-deficient mice

Because IL-2R-deficient mice have decreased numbers of mature V3⁺ thymocytes and lack DETC (37), the IL-2R plays an essential role in the development of V3⁺ T cells in the fetal thymus and the skin. To test the role of the IL-2R in proliferation and survival of V3⁺ T cells, we introduced the V3/V1 TCR transgene into IL-2R-deficient mice to bypass V-J recombination and to help keep the expression of the TCR. We first analyzed adult thymocytes by flow cytometry (Fig. 7A). There was no significant difference in V3⁺ T cells between TCR-Tg⁺IL-2R^+/- and TCR-Tg⁺IL-2R^-/- mice. The numbers of V3⁺ thymocytes were also unchanged (Fig. 7B). These results suggest that IL-2R is dispensable for expansion of V3⁺ T cells in the adult thymus.

View larger version (44K): [in this window] [in a new window]   FIGURE 7. Tg T cell development is not blocked in the adult thymus of IL-2R-deficient mice. A, Thymocytes were isolated from V3/V1 TCR-Tg+IL-2R+/- and V3/V1 TCR-Tg+IL-2R-/- mice and stained with FITC-anti-TCR and PE-anti-V3/V1 TCR Abs. The percentages of cells for a given phenotype are shown. The data are representative of four mice of each genotype (5-wk-old littermates). B, Numbers of total and V3+ T cells were counted in the thymus from V3/V1 TCR-Tg+IL-2R+/- and V3/V1 TCR-Tg+IL-2R-/- 5-wk-old mice. The mean ± SE is calculated from four mice. The numbers of V3+ T cells were calculated from the total cell numbers and the percentage of V3+ cells in each mouse.

View larger version (67K): [in this window] [in a new window]   FIGURE 8. The V3/V1 TCR and Bcl-2 transgenes fail to restore DETC in the skin of IL-2R-deficient mice. Epidermal sheets of 5-wk-old mice were stained with either FITC-anti-Thy-1.2 or FITC-anti-V3/V1 TCR Ab and examined under a fluorescence microscope.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

The IL-7R transmits at least two signals during T cell development. One is for proliferation and survival, and the other is for recombination and transcription of the TCR locus. As we and others previously showed, the V-J recombination of TCR genes was severely impaired in IL-7R-deficient mice (28, 29). In addition, STAT5, a signaling molecule of the IL-7R, induced germline transcription in the TCR locus and promoted V-J recombination and T cell development (31). In this study, the V3/V1 transgene completely rescued DETC in the fetal thymus and the skin of IL-7R-deficient mice. These results suggest that the IL-7R is essential for recombination of TCR genes even in the fetal thymus. This is probably because the IL-2/IL-15R is not expressed at very early stages when V(D)J recombination takes place.

Thymic T cell development depends on IL-7R signaling for both proliferation and survival. In previous reports, the IL-7R induced the expression of Bcl-2 in T cell precursors (21), and introduction of a Bcl-2 transgene partly restored T cell development in IL-7R-deficient mice (22, 23). This is probably because T cell precursors receive proliferation and survival signals from pre-TCR after they manage to express TCR -chain (47). In contrast, T cell precursors seem to depend entirely on the IL-7R for their proliferation and survival in the thymus. The Bcl-2 transgene had a minimal effect on T cells in the thymus of V3/V1 TCR-Tg⁺IL-7R^-/- mice (Fig. 3), in accordance with the previous reports that Bcl-2 transgenes did not rescue T cells in IL-7R^-/- and _c^-/- mice (31, 48). Therefore, T cell precursors receive proliferation and survival signals from the IL-7R mainly irrespective of Bcl-2. This can be mediated by a carboxyl-terminal region of the IL-7R through the activation of PI3 kinase and Pim-1 (25, 49, 50). It is also conceivable that the IL-7R supports the survival of T cells by keeping the transcription of the TCR genes (30). Because the TCR transgene expression on recovered T cells was not lowered, our results suggest that impaired expression of the transgene alone would not explain the defective development of T cells in these mice.

Extrathymic T cell development depends not only on the IL-7R but also on the IL-2/IL-15R. Although IL-7R-deficient mice completely lack IEL (18), IL-15-, IL-15R-, and IL-2R-deficient mice show only decreased numbers of IEL (33, 34, 35). Because a V2/V5 TCR transgene did not completely rescue IEL in IL-7R-deficient mice, it is implied that the IL-7R promotes proliferation and/or survival of IEL besides inducing recombination of TCR genes (S.-K. Ye and K. Ikuta, unpublished data). In addition, IEL probably receive proliferation and survival signals from the IL-2/IL-15R in response to IL-15 produced by intestinal epithelial cells. Thus, the IL-7R and the IL-2/IL-15R play their roles at early and late stages of IEL development, respectively.

DETC development has unique features. The V3/V1 TCR transgene completely rescued V3⁺ DETC in the fetal thymus and the skin of IL-7R-deficient mice. In contrast, the same transgene failed to restore DETC in the skin of IL-2R-deficient mice. These results supported the idea that the IL-2/IL-15R plays an essential role either in maturation of V3⁺ T cells in the fetal thymus or in expansion and/or survival of DETC in the skin (37). Because IL-2R-deficient mice had only decreased numbers of mature V3⁺ T cells in the fetal thymus, the main reason for the lack of DETC in V3/V1⁺IL-2R^-/- mice would be that DETC and their precursors depend mostly on the IL-2/IL-15R for their proliferation and survival in the skin. Because the Bcl-2 transgene did not restore DETC in the skin of V3/V1⁺IL-2R^-/- mice, DETC are likely to receive a proliferation signal from the IL-2R even in the skin. These results are consistent with our previous results that exogenous addition of IL-15 to organ culture of fetal skin induced proliferation of V3 DETC (37).

	Acknowledgments

 
We thank Drs. M. Iwashima, S. Sakaguchi, I. MacNeil, J. Domen, K. Akashi, and I. L. Weissman for materials and discussion; M. Iidaka, M. Sugimori, Y. Kobayashi, T. Taniuchi, and M. Tanaka for their excellent technical assistance; and Dr. S. Takeda for critically reading the manuscript.

	Footnotes

 
¹ This study was supported by grants-in-aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and by the grant provided by the Ichiro Kanehara Foundation.

² Current address: Department of Immune Regulation, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.

³ Address correspondence and reprint requests to Dr. Koichi Ikuta, Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. E-mail address: ikuta{at}mfour.med.kyoto-u.ac.jp

⁴ Abbreviations used in this paper: DETC, dendritic epidermal T cells; IEL, intestinal intraepithelial lymphocytes; _c, common cytokine receptor -chain; PI, phosphatidylinositol; Jak, Janus kinase; Tg, transgenic.

Received for publication March 23, 2001. Accepted for publication June 11, 2001.

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