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, 98 (5), 2577-81

Requirement for Natural Killer T (NKT) Cells in the Induction of Allograft Tolerance

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Requirement for Natural Killer T (NKT) Cells in the Induction of Allograft Tolerance

K I Seino et al. Proc Natl Acad Sci U S A.

Abstract

In this study, we investigated the role of Valpha14 natural killer T (NKT) cells in transplant immunity. The ability to reject allografts was not significantly different between wild-type (WT) and Valpha14 NKT cell-deficient mice. However, in models in which tolerance was induced against cardiac allografts by blockade of lymphocyte function-associated antigen-1/intercellular adhesion molecule-1 or CD28/B7 interactions, long-term acceptance of the grafts was observed only in WT but not Valpha14 NKT cell-deficient mice. Adoptive transfer with Valpha14 NKT cells restored long-term acceptance of allografts in Valpha14 NKT cell-deficient mice. The critical role of Valpha14 NKT cells to mediate immunosuppression was also observed in vitro in mixed lymphocyte cultures in which lymphocyte function-associated antigen-1/intercellular adhesion molecule-1 or CD28/B7 interactions were blocked. Experiments using IL-4- or IFN-gamma-deficient mice suggested a critical contribution of IFN-gamma to the Valpha14 NKT cell-mediated allograft acceptance in vivo. These results indicate a critical contribution of Valpha14 NKT cells to the induction of allograft tolerance and provide a useful model to investigate the regulatory role of Valpha14 NKT cells in various immune responses.

Figures

Figure 1
Figure 1
Vα14 NKT cells are required for anti-LFA-1/ICAM-1- or anti-B7–1/B7–2-induced cardiac allograft tolerance. BALB/c hearts were transplanted into WT or NKT KO B6 mice. (A) Some recipients received anti-LFA-1/ICAM-1 mAbs for the first 5 days after transplantation. Some NKT KO recipients were transferred with Vα14 NKT cells before transplantation. (B) Both WT and NKT KO recipients received anti-B7–1/B7–2 mAbs for the first 5 days after transplantation. Similar results were obtained in two independent experiments.
Figure 2
Figure 2
Involvement of Vα14 NKT cells in suppression of proliferative response against donor alloantigens by anti-LFA-1/ICAM-1 or anti-B7–1/B7–2 mAbs in vitro. Splenocytes (2 × 105 cells) from WT (closed bars) or NKT KO (striped bars) B6 mice were cocultured with mitomycin C-treated CD1d KO BALB/c splenocytes (2 × 105 cells) in the presence or absence of the indicated doses of anti-LFA-1/ICAM-1 or anti-B7–1/B7–2 mAbs. To some cultures of NKT KO responder cells, splenocytes (6,000 cells) from NKT TG mice were added. After 5 days, [3H]thymidine uptake was assessed for the last 8 h. Data represent mean ± SE of four wells. Similar results were obtained in three independent experiments. *, P < 0.05 compared with WT at each mAb dose. NS, not significantly different from WT at each mAb dose.
Figure 3
Figure 3
Quantitative analysis of apoptosis of alloreactive responder cells in vitro. Splenocytes (2 × 106 cells) from WT (Left) or NKT KO (Right) B6 mice were cocultured with mitomycin C-treated BALB/c splenocytes (2 × 106 cells) in 6-well flat-bottomed plates in the presence or absence of 1 μg/ml each of anti-LFA-1/ICAM-1 or anti-B7–1/B7–2 mAbs. After 2–4 days, the cells were collected and stained with FITC-labeled anti-H-2Kb mAb and phycoerythrin-labeled annexin V. The proportion of annexin V-positive apoptotic cells in the H-2Kb-positive responder cells was determined by fluorescence-activated cell sorter (FACS) Calibur. Data represent mean of four wells. Similar results were obtained in three independent experiments.

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