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Dominant transplantation tolerance impairs CD8+ T cell function but not expansion

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Abstract

Alloreactive CD8+ T cells may persist in animals made tolerant of transplanted tissues; their function is controlled through continuous censorship by regulatory CD4+ T cells. We sought to establish the stage at which such censorship operates. We found that monospecific CD8+ T cells introduced into tolerant animals responded to the tolerated tissue antigen as if they had received CD4+ T cell “help”: they proliferated and accumulated normally. However, they did show compromised graft rejection, interferon-γ production and cell-mediated cytotoxicity. These findings suggest that tolerance mediated by regulatory T cells acts by censoring immune effector functions rather than by limiting the induction of T cell responses.

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Acknowledgements

We thank S. Humm for preparing many of the mAbs used in vivo and the PSB staff—especially M. Coates, K. Steventon and S. Laynes. Supported by a program grant from the Medical Research Council, UK and the Chang-Gung Memorial Hospital, Taiwan (to C. L.).

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Competing interests

The authors declare no competing financial interests.

Correspondence to Herman Waldmann.

Supplementary information

  1. Web Fig. 1.

    Tolerance induction to fully mismatched skin allografts. CBA mice were treated with three doses of 1 mg of the anti-CD4, anti-CD8 and anti-CD154 nondepleting mAbs over 1 week following B10 skin transplantation at day 0. These mice accepted the allografts indefinitely as well as new B10 skin transplants grafted at day 100 (filled squares, n = 6, MST > 200 days). The same mice remained competent to reject third-party BALB/c skin grafts, transplanted at day 145 (open squares, n = 6, MST = 16 days). Mice treated with the same mAbs without an initial tolerising skin allograft, rejected B10 skin grafts when transplanted at day 100 (filled triangles, n = 5, MST = 16 days) as well as BALB/c grafts transplanted at day 145 (open triangles, n = 5, MST = 15 days). Untreated controls readily rejected B10 skin allografts (filled circles, n = 10, MST = 10 days). (PDF 114 kb)

  2. Web Fig. 2.

    An agonist CD40 mAb can bypass help for CD8+ T cell expansion. Euthymic or thymectomized and CD4-depleted CBA mice were injected intravenously with 1 × 107 CFSE-labeled Des+ CD8+ T cells. The following day, mice were immunized intravenously with 1 × 106 (CBA × B10)F1 APCs or no APCs as a control. In addition, some mice received agonist CD40 mAb (FGK-45, 1 mg per mice) by i.p. injection. (a) The average number of divisions was calculated by the equation listed in the Methods. (b) Total number of Des+ CD8+ T cells in spleens of host mice. Six mice were included in each group. Data were pooled from three independent experiments. (PDF 129 kb)

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DOI

https://doi.org/10.1038/ni853

Further reading

Figure 1: Graft survival despite CD8+ T cell proliferation in tolerized animals.
Figure 2: Limited expansion of monospecific CD8+ T cells without CD4+ T cell help.
Figure 3: CD4+ T cell help enhances graft rejection by monospecific CD8+ T cells.
Figure 4: Monospecific CD8+ T cells can expand in tolerized mice.
Figure 5: IFN-γ production and CTL activity is censored in tolerized hosts.