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Immunology and Transplantation

In Vivo Control of Diabetogenic T-Cells by Regulatory CD4+CD25+ T-Cells Expressing Foxp3

  1. Dorthe Lundsgaard,
  2. Thomas Lindebo Holm,
  3. Lars Hornum and
  4. Helle Markholst
  1. From the Hagedorn Research Institute, Gentofte, Denmark
  1. Address correspondence and reprint requests to Helle Markholst, MD, Hagedorn Research Institute, Niels Steensens Vej 6, DK-2820, Gentofte, Denmark. E-mail: hmar{at}hagedorn.dk
Diabetes 2005 Apr; 54(4): 1040-1047. https://doi.org/10.2337/diabetes.54.4.1040
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  • FIG. 1.
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    FIG. 1.

    Prevention of accelerated diabetes by prior transfer of unpurified leukocytes. DP-BB rats (age 26–33 days) received 10 × 106 diabetogenic T-cells (D); one group (n = 34) received no protective transfer. Unpurified protective cells containing 64 × 106 T-cells (P) significantly affected diabetes onset compared with no protective cells when protective cells were transferred 2 (n = 8; P < 0.05), 3 (n = 4; P < 0.002), or 4 (n = 10; P < 0.0001) days before transfer of diabetogenic cells. Data are pooled from four experiments. The dashed line (n = 491) is the spontaneous diabetes incidence in DP-BB rats reared within the same room at the same time.

  • FIG. 2.
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    FIG. 2.

    Tracking of CTO-labeled diabetogenic T-cells and CFDA-SE−labeled protective CD4+ T-cells after transfer. A: Ratio of diabetogenic donor T-cells to recipient T-cells on day 2 or 4 after transfer of diabetogenic cells (n = 6). *P < 0.05 vs. cLNs and spleen; †P < 0.05 vs. mLNs, cLNs, and spleen. B: Representative fluorescence-activated cell sorter (FACS) dot plot (of n = 9) displaying all live T-cells in panLNs 2 days after transfer of diabetogenic cells. Recipient T-cells were double negative. C: Representative FACS dot plot (of n = 3) from recipient that had received CD4+ protective T-cells 7 days earlier.

  • FIG. 3.
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    FIG. 3.

    Prevention of accelerated diabetes by CD25+ and CD25− subsets. Rats received 3 × 106 diabetes-inducing T-cells. A: Transfer 4 days before. Purified CD4+CD25+ or CD4+CD25− T-cells significantly affected diabetes onset (P < 0.0004 and P < 0.006, respectively) when transferred to prediabetic DP-BB rats age 29–33 days. The rats received no protective transfer (n = 8), 20 × 106 CD4+CD25− T-cells (n = 8), or 2 × 106 CD4+CD25+ T-cells (n = 6). Data are pooled from two experiments. B: Simultaneous transfer. Purified CD4+CD25+ T-cells significantly affected diabetes onset (P < 0.001), whereas CD4+CD25− T-cells did not (NS) when transferred to prediabetic DP-BB rats age 27–29 days. The rats received no protective transfer (n = 9), 20 × 106 CD4+CD25− T-cells (n = 11), or 2 × 106 CD4+CD25+ T-cells (n = 12). Data are pooled from two experiments.

  • FIG. 4.
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    FIG. 4.

    Prevention of spontaneous diabetes by CD25+ and CD25− subsets. DP-BB rats (n = 52) received protective transfers of purified CD4+CD25+ or CD4+CD25− T-cells. Data are pooled from three experiments. The dashed line (n = 491) is the spontaneous diabetes incidence in DP-BB rats reared within the same room at the same time. A: Transfer of protective subsets at age 27 ± 2 days. Transfer of 2 × 106 CD4+CD25+ T-cells (n = 14; P < 0.0001) and 20 × 106 CD4+CD25− T-cells (n = 18; P < 0.0001) significantly affected diabetes onset compared with no transfer. There was no significant difference between the two test groups. B: Transfer of protective subsets at age 42 days. Transfer of 2 × 106 CD4+CD25+ T-cells (n = 10; P < 0.0001) and 20 × 106 CD4+CD25− T-cells (n = 10; P < 0.0004) significantly affected diabetes onset compared with no transfer. There was a significant difference between the two test groups (P < 0.004).

  • FIG. 5.
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    FIG. 5.

    Semiquantitative RT-PCR of rat Foxp3 in CD4+CD25+ or CD4+CD25− subsets. Data are means + SD of four different sets of purified cells (each set tested in triplicate).

Tables

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  • TABLE 1

    Accelerated diabetes after transfer of purified, diabetogenic T-cells

    No transfer3 × 106 cells5 × 106 cells10 × 106 cells23 × 106 cells
    Diabetes incidence455 of 491 (93)18 of 18 (100)30 of 30 (100)32 of 34 (94)3 of 3 (100)
    Median age (days) at diabetes onset76 (72–81)*58 (56–61)†52 (50–54)‡50 (46–53)§47
    • Data are n (%) or median (interquartile range) and were pooled from 14 experiments.

    • *

      * P < 0.0001 vs. 3, 5, 10, and 23 × 106 cells;

    • †

      † P < 0.0004 vs. 5 × 106 cells, P < 0.0023 vs. 10 × 106 cells, and P < 0.0001 vs. 23 × 106 cells;

    • ‡

      ‡ P < 0.0001 vs. 23 × 106 cells, but NS vs. 10 × 106 cells;

    • §

      § NS vs. 23 × 106 cells.

  • TABLE 2

    Prevention of accelerated diabetes by prior transfer of pure CD4+ T cells

    GroupDiabetogenic T-cells (×106)Protective CD4+ T-cells (×106)RatsRats rendered diabetic before age 120 daysDegree of protection against diabetes (%)Age at diabetes onset (days)
    1A5None12120*52 (49–53)
    1BNone43100100—
    1C5431119182
    1D521.520100—
    2A3None10100†58 (58–59)
    2B321.530100—
    2C3106183109
    • Data are median (interquartile range) unless otherwise indicated. DP-BB rats (age 32–35 days) received CD4+ T-cells in the indicated amounts. After 4 days, diabetes-inducing T-cells were transferred in the indicated amounts. Data are pooled from four experiments.

    • *

      * P < 0.0001 vs. groups 1B and 1C, P < 0.0175 vs. group 1D;

    • †

      † P < 0.0045 vs. group 2B, P < 0.0003 vs. group 2C.

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In Vivo Control of Diabetogenic T-Cells by Regulatory CD4+CD25+ T-Cells Expressing Foxp3
Dorthe Lundsgaard, Thomas Lindebo Holm, Lars Hornum, Helle Markholst
Diabetes Apr 2005, 54 (4) 1040-1047; DOI: 10.2337/diabetes.54.4.1040

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In Vivo Control of Diabetogenic T-Cells by Regulatory CD4+CD25+ T-Cells Expressing Foxp3
Dorthe Lundsgaard, Thomas Lindebo Holm, Lars Hornum, Helle Markholst
Diabetes Apr 2005, 54 (4) 1040-1047; DOI: 10.2337/diabetes.54.4.1040
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