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Induction of Tumor Immunity by Removing CD25+CD4+ T Cells: A Common Basis Between Tumor Immunity and Autoimmunity

Jun Shimizu, Sayuri Yamazaki and Shimon Sakaguchi
J Immunol November 15, 1999, 163 (10) 5211-5218;
Jun Shimizu
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Sayuri Yamazaki
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Shimon Sakaguchi
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  •   FIGURE 1.
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    FIGURE 1.

    Eradication of tumor transplants in nude mice by transferring CD25+ cell-depleted splenic cell (CD25− cell) suspensions. A, Tumor growth was monitored for individual BALB/c nude mice s.c. transplanted with 1.5 × 105 RL♂1 cells (arrow) immediately after i.v. transfer of 3 × 107 untreated spleen cells (upper panel), 3 × 107 CD25− spleen cells (middle panel), or mixtures of CD25− spleen cells (3 × 107) and CD4+ spleen cells (1 × 107) (lower panel). The CD25− spleen cell-transferred nude mice having rejected the tumors were rechallenged on day 60 (arrow) with 10 times larger dose (1.5 × 106) of RL♂1 cells and monitored for tumor growth (middle panel). Insets show staining of each cell inoculum with FITC-labeled anti-CD4 Ab (ordinate) and PE-labeled anti-CD25 Ab (abscissa) (logarithmic scale). B, Percentage of mice surviving in each group (n = 9) on various days after tumor transplantation (total of three independent experiments).

  •   FIGURE 2.
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    FIGURE 2.

    Two types of tumor-killing activity in the nude mice having rejected tumors after transfer of CD25− cells. A, Spleen cells from individual nude mice (n = 6) that had received CD25− cells and rejected RL♂1 (as shown in Fig. 1) were cultured for 7 days with or without RL♂1 (filled or open circles, respectively) and assessed for killing activity against RL♂1 or B16. The group of mice enclosed with circles or rectangles (designated I or II, respectively) in the right and left figures are the same. Dotted lines connect cytotoxic activities of RL♂1-stimulated or nonstimulated cultures from the same mice. B, Activity to kill RL♂1 or B16 in each representative mouse from the group enclosed with circles (type I) or rectangles (type II) in A is shown. Spleen cells from each mouse were cultured for 7 days with (•) or without RL♂1 (○). C, CD4/CD8 phenotype of cytotoxic cells. Individual mice from group I or II in A were assessed for cytotoxic activity at E:T ratio of 100 after depleting CD4+ cells, CD8+ cells, or both (designated CD4− cells, CD8− cells, or CD4−8− cells, respectively) from the spleen cells cultured for 7 days with RL♂1, as shown in B.

  •   FIGURE 3.
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    FIGURE 3.

    Induction of tumor immunity by administering anti-CD25 mAb to normal mice. Eight-week-old BALB/c or B6 mice were i.v. injected with 1 mg each of purified PC61 on 4 and 2 days (filled arrows) before s.c. inoculation of 1 × 105 RL♂1 or B16 cells (open arrow), and tumor growth was monitored for individual mice (five mice per group).

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    FIGURE 4.

    In vitro induction of cytotoxic lymphocytes by eliminating CD25+4+ T cells. A, CD25− or uneliminated spleen cells prepared from normal BALB/c mice were cultured with or without RL♂1 for 5 or 7 days and assessed for activity to kill RL♂1 at E:T ratio of 100. Each circle represents the activity of a single culture. Vertical bars are SDs of the mean. The inset shows a representative cytotoxic activity of CD25− (square) or uneliminated (circle) spleen cells, or CD25− cells mixed with purified CD25+CD4+ T cells (triangle), cultured for 7 days with (filled symbols) or without RL♂1 (open symbols). B, CD25− spleen cells from various strains were cultured for 7 days and assessed at E:T ratio of 100 for activity to kill various syngeneic or allogeneic tumor cells. Average activity of four independent experiments and SDs is shown.

  •   FIGURE 5.
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    FIGURE 5.

    In vitro generation of TCR− CD4−8− NK cells. A, BALB/c CD25− cells were cultured for 7 days without tumor stimulation and assessed for activity to kill RL♂1 (○) or B16 (•) after depleting CD4+ cells, CD8+ cells, or both, by treating cells with specific Ab and C: a, C treatment alone; b, anti-CD4 and C; c, anti-CD8 and C; d, anti-CD4, anti-CD8, and C. The results of five independent experiments are shown. B, Anti-CD4 (○), anti-CD8 (•), anti-α/β-TCR (□), or anti-γ/δ-TCR Ab (▵) was added at various concentrations to the cytotoxicity assay with BALB/c CD25− cells cultured for 7 days and RL♂1 cells as the targets. As a positive control of blocking by anti-CD8 or anti-α/β-TCR Ab, Abs were added to the killing of RL♂1 cells by B6 spleen cells stimulated for 7 days with allogeneic RL♂1 cells (asterisks). A representative result of three independent experiments is shown. C, CD25− spleen cells from B6 mice were depleted of B cells, cultured for 7 days with APCs, and stained with FITC anti-CD4, PE anti-CD8, and biotinylated anti-α/β-TCR, anti-γ/δ-TCR, or anti-NK1.1 Ab with Cy5-streptavidin as the secondary reagent. Expression of α/β-TCR, γ/δ-TCR, or NK1.1 on CD4−8− cells in the left figure is shown as histograms (abscissa is staining intensity in logarithmic scale; ordinate is the number of cells as arbitrary units). A representative staining of three independent experiments is shown.

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    FIGURE 6.

    Absence of promiscuous killing activity of cultured CD25− cells in beige mice. CD25− or uneliminated spleen cells from B6-bg or B6 mice were cultured for 7 days, and assessed for killing activity against RL♂1 or B16 cells. Allospecific killing activity (asterisks) of uneliminated B6-bg or B6 spleen cells stimulated for 7 days with RL♂1 was also assessed against RL♂1 cells as the targets.

  •   FIGURE 7.
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    FIGURE 7.

    Requirement of CD25−4+ T cells or IL-2 for induction of CD4−8− NK cells. A and B, CD25− or uneliminated BALB/c spleen cells (filled or open circle, respectively) were cultured for various days and assessed for proliferative activity (A) and IL-2 activity in supernatants (B). These activities in the culture of CD25− cells were also assessed after depleting CD4+ cells or CD8+ cells (filled or open triangle, respectively) on day 7 or 5 at the peak of proliferation or IL-2 secretion, respectively. C, Pan anti-class II MHC mAb (CA4) or control rat IgG was added at graded concentrations to 1-wk culture of CD25− or uneliminated BALB/c spleen cells (filled or open columns, respectively) and assessed for the effect on proliferation. D, BALB/c spleen cells were depleted of a particular cell population(s) by treatment with specific Ab and C, then cultured for 7 days and assessed for activity to kill RL♂1 at E:T ratio of 100. Treatments of spleen cells before culture were as follows: a, C treatment alone; b, anti-CD25 and C; c, anti-CD25, anti-CD8, and C; d, anti-CD25, anti-CD4, and C; e, anti-CD4, anti-CD8, and C. IL-2 (1000 U/ml) was added to the culture of spleen cells treated with: f, anti-CD25, anti-CD4 Ab plus C; g, anti-CD4, anti-CD8 Ab plus C; or h, C alone. A representative result of three independent experiments is shown.

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    FIGURE 8.

    Inability of CD25−4+ T cells from IL-2-deficient mice to generate LAK/NK-like cells from normal CD4−8− cells. CD25−4+ spleen cells from IL-2−/−, IL-4−/−, IFN-γ−/−, or control BALB/c mice were mixed with an equal number of CD4−8− spleen cells prepared from normal BALB/c mice, cultured for 7 days, and assessed for the activity to kill RL♂1 or B16 cells. A representative result of three independent experiments is shown.

  •   FIGURE 9.
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    FIGURE 9.

    Development of autoimmunity in nude mice after inoculation of CD25− cells. BALB/c nude mice received CD25− BALB/c spleen cells and inoculation of RL♂1 cells, as shown in Fig. 1. Other groups of mice received uneliminated, CD4+ cell-depleted (i.e., CD4−), or CD4+ cell- and CD8+ cell-depleted (i.e., CD4−8−) cell suspensions (1 × 107 cells) prepared from CD25− cells cultured for 7 days. Three months after transfer, mice were assessed for histological development of gastritis (circle) and/or thyroiditis (triangle), and titers of autoantibodies specific for gastric parietal cells or thyroglobulins. Filled symbols mean grade 2 (severe) gastritis or thyroiditis; shaded symbols, grade 1 (mild) gastritis or thyroiditis; open symbols, intact gastric mucosa or thyroid glands.

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The Journal of Immunology: 163 (10)
The Journal of Immunology
Vol. 163, Issue 10
15 Nov 1999
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Induction of Tumor Immunity by Removing CD25+CD4+ T Cells: A Common Basis Between Tumor Immunity and Autoimmunity
Jun Shimizu, Sayuri Yamazaki, Shimon Sakaguchi
The Journal of Immunology November 15, 1999, 163 (10) 5211-5218;

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Induction of Tumor Immunity by Removing CD25+CD4+ T Cells: A Common Basis Between Tumor Immunity and Autoimmunity
Jun Shimizu, Sayuri Yamazaki, Shimon Sakaguchi
The Journal of Immunology November 15, 1999, 163 (10) 5211-5218;
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